Caloric Restriction Versus a Diet High in Antioxidants: Are they Equipotent in Altering or Reversing the Course of Aging?

  • Gemma Casadesus
  • Barbara Shukitt-Hale
  • Mark A. Smith
  • Heather M. Stellwagen
  • James A. Joseph


Currently, little is known about the mechanisms responsible for the neuronal degeneration seen during both normal aging and neurodegenerative disease; however, among the prime candidates responsible for producing these effects are free radicals. It has been hypothesized that brain aging results from a progressive inability to cope with such insults as oxidative stress and inflammation. As a result there is a fertile environment for the subsequent development of neurodegenerative disease. Therefore, if the preservation of neuronal function and associated cognitive and motor performance during aging will enhance the probability of aging successfully, then it is of crucial importance to find ways to preserve or decrease the responsiveness of the brain to these insults. One method that has a long history of being very effective in preventing age-related declines in numerous systems in rodents and other lower species and indeed can even increase longevity, is that of caloric restriction. However, although evidence suggests that this procedure also may have similar effects in infrahuman primates, its applicability to humans remains questionable, especially with respect to the issue of compliance. Recent studies indicate that alterations in the quality of the diet in terms of adding more antioxidant-containing foods may be just as effective as decreasing the amount of calories in reducing the effects of aging. The purpose of this review is to compare and contrast these two strategies, in terms of their effectiveness, safety, and generalized applicability for the human condition.


Caloric restriction Antioxidants Dietary supplementation Oxidative stress Alzheimer’s Disease Phytonutrients Aging 


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  1. Bastianetto, S., Ramassamy, C., Dore, S., Christen, Y., Poirier, J., & Quirion, R. (2000). The Gingko biloba e`xtract (Efb 761) protects hippocampal neurons against cell death induced by beta-amyloid. Eur J Neurosci 12: 1882–1890.PubMedGoogle Scholar
  2. Beatty, W. W., Clouse, B. A. & Bierley, R. A. (1987). Effects of long-term restricted feeding on radial maze performance by aged rats. Neurobiol Aging 8: 325–7.PubMedGoogle Scholar
  3. Bellush, L. L., Wright, A. M., Walker, J. P., Kopchick, J. & Colvin, R. A. (1996). Caloric restriction and spatial learning in old mice. Physiol Behav 60: 541–7.PubMedGoogle Scholar
  4. Bickford, P. C., Gould, T., Briederick, L., Chadman, K., Pollock, A., Young, D., Shukitt-Hale, B. & Joseph, J. (2000). Antioxidant-rich diets improve cerebellar physiology and motor learning in aged rats. Brain Res 866: 211–7.PubMedGoogle Scholar
  5. Bickford, P. C., Shukitt-Hale, B. & Joseph, J. (1999). Effects of aging on cerebellar noradrenergic function and motor learning: nutritional interventions. Mech Ageing Dev 111: 141–54.PubMedGoogle Scholar
  6. Blackwell, B. N., Bucci, T. J., Hart, R. W. & Turturro, A. (1995). Longevity, body weight, and neoplasia in ad libitum-fed and diet- restricted C57BL6 mice fed NIH-31 open formula diet. Toxicol Pathol 23(5): 570–82.PubMedGoogle Scholar
  7. Bridi, R., Crossetti, F. P., Steffen, V. M., & Henriques, A. T. (2001). The antioxidant activity of standardized extract of Ginkgo biloba (EGb 761) in rats. Phytother Res 15: 44–451.Google Scholar
  8. Bronner, W. E. & Beecher, G. R. (1995). Extraction and measurement of prominent flavonoids in orange and grapefruit juice concentrates. J. Chrom. 705: 247–256.Google Scholar
  9. Cantuti-Castelvetri, I., Shukitt-Hale, B. & Joseph, J. A. (2000). Neurobehavioral aspects of antioxidants in aging. Int J Dev Neurosci 18: 367–81.PubMedGoogle Scholar
  10. Cao, G., Sofie, E. & Prior, R. L. (1996). Antioxidant capacity of tea and common vegetables. J. Agric. Food Chem. 44: 3426–3431.Google Scholar
  11. Cao, G., Verdon, C. P., Wu, A. H. B., Wang, H. & Prior, R. L. (1995). Automated assay of oxygen radical absorbance capacity with the COBAS FARAII. Clin. Chem. 41: 1738–1744.PubMedGoogle Scholar
  12. Caperle, M., Maiani, G., Azzini, E., Conti, E. M., Raguzzini, A., Ramazzotti, V. & Crespi, M. (1996). Dietary profiles and anti-oxidants in a rural population of central Italy with a low frequency of cancer. Eur J Cancer Prev 5: 197–206.PubMedGoogle Scholar
  13. Choi, J. H., Kim, D. W. & Yu, B. (1998). Modulation of age-related alterations of iron, ferritin, and lipid peroxidation in rat brain synaptosomes. J Nutr Health Aging 2: 133–7.PubMedGoogle Scholar
  14. Christen, Y. (2000). Oxidative stress and Alzheimer disease. American Journal of Clinical Nutrition 71: 621S–629S.PubMedGoogle Scholar
  15. Cook, C. I. & Yu, B. P. (1998). Iron accumulation in aging: modulation by dietary restriction. Mech Ageing Dev 102: 1–13.PubMedGoogle Scholar
  16. Corral-Debrinski, M., Horton, T., Lott, M. T., Shoffner, J. M., Beal, M. F. & Wallace, D. C. (1992). Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nat Genet 2: 324–9.PubMedGoogle Scholar
  17. Corwin, R. L., Wojnicki, F. H., Fisher, J. O., Dimitriou, S. G., Rice, H. B., & Young, M. A. (1998). Limited access to a dietary fat option affects ingestive behavior but not body composition in male rats. Physiol Behav 65: 545–553.PubMedGoogle Scholar
  18. DeFeudis, F. V. & Drieu, K. (2000). Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. Curr Drug Targets 1: 25–58.PubMedGoogle Scholar
  19. Denisova, N., Bielinski, D., Shukitt-Hale, B., Gordon, M., Morgan, D., Diamond, D., Arendash, G., & Joseph, J.A. (2001). Membrane and signaling effects in blueberry-supplemented APP/PS-1 mice: Relation to behavior. Soc. Neurosci. Abs. 27, 649.13.Google Scholar
  20. Drieu, K. (1986). Preparation and definition of Ginkgo biloba extract. Presse Med 15: 1455–7.PubMedGoogle Scholar
  21. Duan, W., Mattson, M.P. (1999). Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson’s disease. J Neurosci Res. 57:195–206.PubMedGoogle Scholar
  22. Duan, W., Lee, J., Guo, Z., & Mattson, M.P. (2001). Dietary restriction stimulates BDNF production in the brain and thereby protects neurons against exchitotoxic injury. J Mol. Neurosci. 16: 1–12.PubMedGoogle Scholar
  23. Dubey, R. K., Tyurina, Y. Y., Turin, V. A., Gillespie, D. G., Branch, R. A., Jackson, E. K. & Kagan, V. E. (1999). Estrogen and tamoxifen metabolites protect smooth muscle cells membrane phospholipids against peroxidation and inhibit cell growth. Circulation Research 84: 229–239.PubMedGoogle Scholar
  24. Dubnov, G., Kohen, R. & Berry, E. M. (2000). Diet restriction in mice causes differential tissue responses in total reducing power and antioxidant compounds. Eur J Nutr 39: 18–30.PubMedGoogle Scholar
  25. Duffy, P. H., Leakey, J. E. A., Pipkin, J. L., Turturro, A. & Hart, R. W. (1997). The Physiologic, Neurologic, and Behavioral Effects of Caloric Restriction Related to Aging, Disease, and Environmental Factors. Environ Res 73: 242–8.PubMedGoogle Scholar
  26. Fahn, S. (1991). An open trial of high-dosage antioxidants in early Parkinson’s disease. Am J Clin Nutr 53: 380S–382S.PubMedGoogle Scholar
  27. Fahn, S. (1992). A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson’s disease. Ann Neurol 32: S128–32.PubMedGoogle Scholar
  28. Felician, O. & Sandson, T. A. (1999). The neurobiology and pharmacotherapy of Alzheimer’s disease. J Neuropsychiatry Clin Neurosci 11: 19–31.PubMedGoogle Scholar
  29. Ferro-Luzzi, A. & Branca, F. (1995). Mediterranean diet, Italian style: prototype of a healthy diet. Am J Clin Nutr 61: 1338S–45S.PubMedGoogle Scholar
  30. Finch, C. E. & Cohen, D. M. (1997). Aging, metabolism, and Alzheimer disease: review and hypotheses. Exp Neurol 143: 82–102.PubMedGoogle Scholar
  31. Forster, M. J., Sohal, B. H. & Sohal, R. S. (2000). Reversible effects of long-term caloric restriction on protein oxidative damage. J Gerontol A Biol Sci Med Sci 55: B522–9.PubMedGoogle Scholar
  32. Fowler, C. J., Cowburn, R. F. & Joseph, J. A. (1997). Alzheimer’s, ageing and amyloid: an absurd allegory? Gerontology 43: 132–42.PubMedGoogle Scholar
  33. Galli, R. L., Bielinski, D., Szprengiel, A., Shukitt-Hale, B., & Joseph, J.A. (2001). Brain regional assessments of inflammatory markers in young and senescent rats. Soc. Neurosci. Abs. 27, 861.1..Google Scholar
  34. Galli, R. L., Casadesus, G., Rottkamp, C., Shukitt-Hale, B., Denisova, N.A., Smith, M.A., & Joseph, J.A. (2000). Immunocytochemical effects in the brains of blueberry supplemented rats showing reversals of age-related cognitive and motor deficits. Soc. Neurosci. Abs. 26, 2078.Google Scholar
  35. Green, M. W., Rogers, P. J., Elliman, N. A. & Gatenby, S. J. (1994). Impairment of cognitive performance associated with dieting and high levels of dietary restraint. Physiol Behav 55: 447–52.PubMedGoogle Scholar
  36. Grodstein, F., Mayeux, R. and Stampfer, M. J. (2000). Tofu and cognitive function: food for thought. J Am Coll Nutr 19: 207–9.PubMedGoogle Scholar
  37. Gsell, W., Reichert, N., Youdim, M. B. & Riederer, P. (1995). Interaction of neuroprotective substances with human brain superoxide dismutase. An in vitro study. Journal of Neural Transmission. Supplementum 45: 271–9.PubMedGoogle Scholar
  38. Harman, D. (1998). Aging and oxidative stress. J Int Fed Clin Chem 10: 24–7.PubMedGoogle Scholar
  39. Hazelton, G. A. & Lang, C. A. (1985). Glutathione peroxidase and reductase activities in the aging mouse. Mech Ageing Dev 29: 71–81.PubMedGoogle Scholar
  40. Heatherton, T. F., Polivy, J., Herman, C. P. & Baumeister, R. F. (1993). Self-awareness, task failure, and disinhibition: how attentional focus affects eating. J Pers 61: 49–61.PubMedGoogle Scholar
  41. Hendrie, H. C., Ogunniyi, A., Hall, K. S., Baiyewu, O., Unverzagt, F. W., Gureje, O., Gao, S., Evans, R. M., Ogunseyinde, A. O., Adeyinka, A. O., Musick, B. & Hui, S. L. (2001). Incidence of dementia and Alzheimer disease in 2 communities: Yoruba residing in Ibadan, Nigeria, and African Americans residing in Indianapolis, Indiana. JAMA 285: 739–47.PubMedGoogle Scholar
  42. Hubert, M. F., Laroque, P., Gillet, J. P. & Keenan, K. P. (2000). The effects of diet, ad Libitum feeding, and moderate and severe dietary restriction on body weight, survival, clinical pathology parameters, and cause of death in control Sprague-Dawley rats. Toxicol Sci 58: 195–207.PubMedGoogle Scholar
  43. Ingram, D. K., Weindruch, R., Spangler, E. L., Freeman, J. R. & Walford, R. L. (1987). Dietary restriction benefits learning and motor performance of aged mice. J Gerontol 42: 78–81.PubMedGoogle Scholar
  44. Jenner, P. and Olanow, W. (1996). Oxidative stress and the pathogenesis of Parkinson’s disease. Neurology 47: S161–S170.PubMedGoogle Scholar
  45. Joseph, J., Shukitt-Hale, B., Denisova, N. A., Martin, A., Perry, G. & Smith, M. A. (2001). Copernicus revisited: amyloid beta in Alzheimer’s disease. Neurobiol Aging 22: 131–46.PubMedGoogle Scholar
  46. Joseph, J. A., Dalton, T. K. & Hunt, W. A. (1988a). Age-related decrements in the muscarinic enhancement of K+ -evoked release of endogenous striatal dopamine: An indicator of altered cholinergic -dopaminergic reciprocal inhibitory control in senescence. Brain Res. 454: 140–148.PubMedGoogle Scholar
  47. Joseph, J. A., Dalton, T. K., Roth, G. S. & Hunt, W. A. (1988b). Alterations in muscarinic control of striatal dopamine autoreceptors in senescence: a deficit at the ligand-muscarinic receptor interface? Brain Res. 454: 149–155.PubMedGoogle Scholar
  48. Joseph, J. A., Denisova, N., Fisher, D., Cantuti-Castelvetri, I. & Erat, S. (1998). Membrane constituencies and receptor subtype contribute to age-related increases in vulnerability to oxidative stress. Prog. Alzheim. Parkin. Dis. 9: 53–58.Google Scholar
  49. Joseph, J. A., Denisova, N., Villalobos-Molina, R., Erat, S. & Strain, J. (1996). Oxidative stress & age-related neuronal deficits. Molec. Chemic. Neuropathol. 28: 35–40.Google Scholar
  50. Joseph, J. A. & Roth, G. S. (1988). Altered striatal dopaminergic and cholinergic reciprocal inhibitory control and motor behavioral decrements in senescence. Ann. NY Acad. Sci. 521: 110–122.PubMedGoogle Scholar
  51. Joseph, J. A. & Roth, G. S. (1988). Upregulation of striatal dopamine receptors and improvement of motor performance in senescence. Ann. NY Acad. Sci. 515: 355–362.PubMedGoogle Scholar
  52. Joseph, J. A., Shukitt-Hale, B., Denisova, N. A., Bielinski, D., Martin, A., McEwen, J. J. & Bickford, P. C. (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: 8114–21.PubMedGoogle Scholar
  53. Joseph, J. A., Shukitt-Hale, B., Denisova, N. A., Prior, R. L., Cao, G., Martin, A., Taglialatela, G. & Bickford, P. C. (1998). Long-term dietary strawberry, spinach, or vitamin E supplementation retards the onset of age-related neuronal signal-transduction and cognitive behavioral deficits. J Neurosci 18: 8047–55.PubMedGoogle Scholar
  54. Joseph, J. A., Villalobos-Molina, R., Denisova, N., Erat, S., Cutler, R. & Strain, J. (1996). Age differences in sensitivity to H2O2 — or no-induced reductions in K+ -Evoked dopamine release from superfused striatal slices: reversals by PBN or trolox. Free Rad. Biol. Med. 20: 821–830.PubMedGoogle Scholar
  55. Joseph, J. A., Villalobos-Molina, R., Denisova, N., Erat, S., Jimenez, N. & Strain, J. (1996). Increased sensitivity to oxidative stress and the loss of muscarinic receptor reponsiveness in senescence. Ann. Ny Acad. Sci. 786: 112–119.PubMedGoogle Scholar
  56. Joseph, J. A., Villalobos-Molina, R., Yamagami, K., Roth, G. S. & Kelly, J. (1995). Age-specific alterations in muscarinic stimulation of K+-evoked dopamine release from striatal slices by cholsterol and S-adenosyl-L-methionine. Brain Res. 673: 185–193.PubMedGoogle Scholar
  57. Joseph, J. A., Whitaker, J., Roth, G. S. & Ingram, D. K. (1983). Life-long dietary restriction affects striatally-mediated behavioral responses in aged rats. Neurobiol Aging 4: 191–6.PubMedGoogle Scholar
  58. Keenan, K. P., Laroque, P., Soper, K. A., Morrissey, R. E. & Dixit, R. (1996). The effects of overfeeding and moderate dietary restriction on Sprague- Dawley rat survival, pathology, carcinogenicity, and the toxicity of pharmaceutical agents. Exp Toxicol Pathol 48: 139–44.PubMedGoogle Scholar
  59. Kitamura, Y., Taniguchi, T. & Shimohama, S. (1999). Apoptotic cell death in neurons and glial cells: implications for Alzheimer’s disease. Jpn J Pharmacol 79: 1–5.PubMedGoogle Scholar
  60. Knipper, M., Leung, L. S., Zhao, D. & Rylett, R. J. (1994). Short-term modulation of glutamatergic synapses in adult rat hippocampus by NGF. Neuroreport 5: 2433–6.PubMedGoogle Scholar
  61. Korte, M., Carroll, P., Wolf, E., Brem, G., Thoenen, H. & Bonhoeffer, T. (1995). Hippocampal long-term potentiation is impaired in mice lacking brain- derived neurotrophic factor. Proc Natl Acad Sci U S A 92: 8856–60.PubMedGoogle Scholar
  62. Krischer, S. M., Eisenmann, M., Bock, A. & Mueller, M. J. (1997). Protein-facilitated export of arachidonic acid from pig neutrophils. J Biol Chem 272: 10601–7.PubMedGoogle Scholar
  63. Landfield, P. W. & Eldridge, J. C. (1994). The glucocorticoid hypothesis of age-related hippocampal neurodegeneration: role of dysregulated intraneuronal Ca2+. Ann. N. Y. Acad. Sci. 746: 308–321.PubMedGoogle Scholar
  64. Launer, L. J. & Kalmijn, S. (1998). Anti-oxidants and cognitive function: a review of clinical and epidemiologic studies. J Neural Transm Suppl 53: 1–8.PubMedGoogle Scholar
  65. Le Bars, P. L., Kieser, M., & Itil, K. Z. (2000). A 26-week analysis of a doubke-blind, placebo controlled trial of the ginkgo biloba extract EGb 761 in dementia. Dement Geriatr Cogn Disord 11: 230–237.PubMedGoogle Scholar
  66. Le Bars, P. L., Katz, M. M., Berman, N., Itil, T. M., Freedman, A. M., & Schatzberg, A. F. (1997). A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. JAMA 278: 1327–1332.PubMedGoogle Scholar
  67. Lee, J., Duan, W., Long, J. M., Ingram, D. K. & Mattson, M. P. (2000). Dietary restriction increases the number of newly generated neural cells, and induces BDNF expression, in the dentate gyrus of rats. J Mol Neurosci 15: 99–108.PubMedGoogle Scholar
  68. Leotsinidis, M., Alexopoulos, A., Schinas, V., Kardara, M. & Kondakis, X. (2000). Plasma retinol and tocopherol levels in greek elderly population from an urban and a rural area: associations with the dietary habits. Eur J Epidemiol 16: 1009–16.PubMedGoogle Scholar
  69. Lessmann, V. (1998). Neurotrophin-dependent modulation of glutamatergic synaptic transmission in the mammalian CNS. Gen Pharmacol 31: 667–74.PubMedGoogle Scholar
  70. Lipman, R. D., Smith, D. E., Bronson, R. T., & Blumberg, J. (1995). Is late-life caloric restriction beneficial? Aging (Milano) 7: 136–139.Google Scholar
  71. Lipmann, R. D., Smith D. E., Blumberg, J. B., & Bronson, R. T. (1998) Effects of caloric restriction or augmentation in adult rats: longevity and lesion biomarkers of aging. Aging (Milano) 10: 463–470.Google Scholar
  72. Liu, J. & Mori, A. (1999). Stress, aging, and brain oxidative damage. Neurochem Res 24: 1479–97.PubMedGoogle Scholar
  73. Lopak, V. & Eikelboom, R. (2000). Pair housing induced feeding suppression: individual housing not novelty. Physiol Behav 71: 329–33.PubMedGoogle Scholar
  74. Lynch, M. A. (1998). Age-related impairment in long-term potentiation in hippocampus: a role for the cytokine, interleukin-1 beta? Progress in Neurobiology 56: 571–89.PubMedGoogle Scholar
  75. Maitra, A., LaVoie, H. A., Day, R. N., Garmey, J. C. & Veldhuis, J. D. (1995). Regulation of porcine granulosa cell 3-hydroxy-3-methylglutaryl coenzyme A reductase by insulin and insulin-like growth factor I: synergism with follicle-stimulating hormone or protein kinase A agonist. Endocrinology 136: 5111–7.PubMedGoogle Scholar
  76. Manev, H. & Uz, T. (1999). Primary cultures of rat cerebellar granule cells as a model to study neuronal 5-lipoxygenase and FLAP gene expression. Ann N Y Acad Sci 890: 183–90.PubMedGoogle Scholar
  77. Marteinsdottir, I., Horrobin, D. F., Stenfors, C, Theodorsson, E., & Mathe, A. A. (1998). Changes in dietary fatty acids alter phospholipid fatty acid consumption in selected regions of rat brain. Prog Neuro-Psychopharm Biol Psych 22: 1007–1021.Google Scholar
  78. Masoro, E. J. (2000). Caloric restriction and aging: an update. Exp Gerontol 35: 299–305.PubMedGoogle Scholar
  79. Mattson, M. P. (2000). Neuroprotective signaling and the aging brain: take away my food and let me run. Brain Res 886: 47–53.PubMedGoogle Scholar
  80. Means, L. W., Higgins, J. L., & Fernandez, T. J. (1993). Mide-life onset of dietary restriction extends life and prolongs cognitive functioning. Physiol Behav 54: 503–508.PubMedGoogle Scholar
  81. Micheau, J. & Riedel, G. (1999). Protein kinases: which one is the memory molecule? Cell Mol Life Sci 55: 534–48.PubMedGoogle Scholar
  82. Minghetti, L. & Levi, G. (1998). Microglia as effector cells in brain damage and repair: focus on prostanoids and nitric oxide. Progress Neurobiol. 54: 99–125.Google Scholar
  83. Mirzoeva, O. K. & Calder, P. C. (1996). The effect of propolis and its components on eicosanoid production during the inflammatory response. Prostaglandins Leukot Essent Fatty Acids 55: 441–9.PubMedGoogle Scholar
  84. Nagata, C. (2000). Ecological study of the association between soy product intake and mortality from cancer and heart disease in Japan. Int J Epidemiol 29: 832–6.PubMedGoogle Scholar
  85. Nicklas, T. A., Baranowski, T., Cullen, K. W., & Berenson, G. (2001). Eating patterns, dietary quality and obesity. J Am Coll Nutr 20: 599–608.PubMedGoogle Scholar
  86. Ogden, J. & Greville, L. (1993). Cognitive changes to preloading in restrained and unrestrained eaters as measured by the Stroop task. Int J Eat Disord 14: 185–95.PubMedGoogle Scholar
  87. Okita, M., Yoshida, S., Yamamoto, J., Suzuki, K., Kaneyuki, T., Kubota, M. & Sasagawa, T. (1995). n-3 and n-6 fatty acid intake and serum phospholipid fatty acid composition in middle-aged women living in rural and urban areas in Okayama Prefecture. J Nutr Sci Vitaminol (Tokyo) 41: 313–23.PubMedGoogle Scholar
  88. Olanow, C. W. (1992). An introduction to the free radical hypothesis in Parkinson’s disease. Ann Neurol 32: S2–9.PubMedGoogle Scholar
  89. Patterson, S. L., Grover, L. M., Schwartzkroin, P. A. & Bothwell, M. (1992). Neurotrophin expression in rat hippocampal slices: a stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs. Neuron 9: 1081–8.PubMedGoogle Scholar
  90. Pedersen, W.A., Culmsee, C., Ziegler, D., Herman, J.P., Mattson, M.P.(1999). Aberrant stress response associated with severe hypoglycemia in a transgenic mouse model of Alzheimer’s disease. J Mol Neurosci 13:159–65.PubMedGoogle Scholar
  91. Pitchumoni, S. S. & Doraiswamy, P. M. (1998). Current status of antioxidant therapy for Alzheimer’s Disease. J Am Geriatr Soc 46: 1566–72.PubMedGoogle Scholar
  92. Pitsikas, N., Carli, M., Fidecka, S. & Algeri, S. (1990). Effect of life-long hypocaloric diet on age-related changes in motor and cognitive behavior in a rat population. Neurobiol Aging 11: 417–23.PubMedGoogle Scholar
  93. Polivy, J. (1996). Psychological consequences of food restriction. J Am Diet Assoc 96: 589–92; quiz 593–4.PubMedGoogle Scholar
  94. Ramassamy, C., Averill, D., Beffert, U., Bastianetto, S., Theroux, L., Lussier-Cacan, S., Cohen, J. S., Christen, Y., Davignon, J., Quirion, R., & Poirier, J. (1999). Oxidative damage and protection by antioxidants in the frontal cortex of Alzheimer’s disease is related to the apolipoprotein E genotype. Free Radical Biol Med 27: 544–535.Google Scholar
  95. Rapp, P. R., Rosenberg, R. A. & Gallagher, M. (1987). An evaluation of spatial information processing in aged rats. Behav. Neurosci. 101: 3–12.Google Scholar
  96. Reiter, C. D., Teng, R. J. & Beckman, J. S. (2000). Superoxide reacts with nitric oxide to nitrate tyrosine at physiological pH via peroxynitrite [In Process Citation]. J Biol Chem 275: 32460–6.PubMedGoogle Scholar
  97. Rodriguez-Palmero, M., Lopez-Sabater, M. C., Castellote-Bargallo, A. I., de la Torre-Boronat, M. C. & Rivero-Urgell, M. (1997). Administration of low doses offish oil derived N-3 fatty acids to elderly subjects. Eur J Clin Nutr 51:554–60.PubMedGoogle Scholar
  98. Rogers, J. (1995). Inflammation as a pathogenic mechanism in Alzheimer’s disease. Arzneimittelforschung 45: 439–42.PubMedGoogle Scholar
  99. Rosenman, S., Shrikant, P., Dubb, L., Benveniste, E. & Ransohoff, R. (1995). Cytokine-induced expression of vascular cell adhesion molecule-1 (VCAM-1) by astrocytes and astrocytoma cell lines. J. Immunol. 154: 1888–1899.PubMedGoogle Scholar
  100. Roth, G. (1995). Changes in tissue responsiveness to hormones and neurotransmitters during aging. Experimental Gerontology. 30: 361–368.PubMedGoogle Scholar
  101. Roth, G. S., Ingram, D. K. & Lane, M. A. (1999). Calorie restriction in primates: will it work and how will we know? J Am Geriatr Soc 47: 896–903.PubMedGoogle Scholar
  102. Schipper, H. (1996). Astrocytes, brain aging, and neurodegeneration. Neurob. Aging 17: 467–480.Google Scholar
  103. Semsei, I., Rao, G. & Richardson, A. (1989). Changes in the expression of superoxide dismutase and catalase as a function of age and dietary restriction. Biochem Biophys Res Commun 164: 620–5.PubMedGoogle Scholar
  104. Sheldon, W. G., Warbritton, A. R., Bucci, T. J. & Turturro, A. (1995). Glaucoma in food-restricted and ad libitum-fed DBA/2NNia mice. Lab Anim Sci 45: 508–18.PubMedGoogle Scholar
  105. Skaper, S. D., Floreani, M., Negro, A., Facci, L. & Giusti, P. (1998). Neurotrophins rescue cerebellar granule neurons from oxidative stress- mediated apoptotic death: selective involvement of phosphatidylinositol 3-kinase and the mitogen-activated protein kinase pathway. J Neurochem 70: 1859–68.PubMedGoogle Scholar
  106. Smith, C. D., Carney, J. M., Starke-Reed, P. E., Oliver, C. N., Stadtman, E. R., Floyd, R. A., Markesbery, W. R. (1991). Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc. Natl. Acad. Sci. 88: 10540–10543.PubMedGoogle Scholar
  107. Smith, M. A., Sayre, L. M., Monnier, V. M. & Perry, G. (1996). Oxidative posttranslational modifications in Alzheimer disease. A possible pathogenic role in the formation of senile plaques and neurofibrillary tangles. Mol Chem Neuropathol 28: 41–8.PubMedGoogle Scholar
  108. Smith, M. A., Siedlak, S. L., Richey, P. L., Mulvihill, P., Ghiso, J., Frangione, B., Tagliavini, F., Giaccone, G., Bugiani, O., Praprotnik, D. & et al. (1995). Tau protein directly interacts with the amyloid beta-protein precursor: implications for Alzheimer’s disease. Nat Med 1: 365–9.PubMedGoogle Scholar
  109. Sofic, E., Lange, K. W., Jellinger, K. & Riederer, P. (1992). Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson’s disease. Neurosci Lett 142: 128–30.PubMedGoogle Scholar
  110. Sohal, R. S., Agarwal, S., Candas, M., Forster, M. J. & Lai, H. (1994b). Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech Ageing Dev 76: 215–24.PubMedGoogle Scholar
  111. Sohal, R. S., Ku, H. H., Agarwal, S., Forster, M. J. & Lai, H. (1994a). Oxidative damage, mitochondrial oxidant generation and antioxidant defenses during aging and in response to food restriction in the mouse. Mech Ageing Dev 74: 121–133.PubMedGoogle Scholar
  112. Sohal, R. S. & Weindruch, R. (1996). Oxidative stress, caloric restriction, and aging. Science 273: 59–63.PubMedGoogle Scholar
  113. Steffen, B., Breier, G., Butcher, E., Schulz, M. & Engelhardt, B. (1996). ICAM-1, VCAM-1, and MAdCAM-1 are expressed on choroid plexus epithelium but not endothelium and mediate binding of lymphocytes in vitro. Am. J. Pathol. 148: 1819–1838.PubMedGoogle Scholar
  114. Stella, N., Estelles, A., Siciliano, J., Tence, M., Desagher, S., Piomelli, D., Glowinski, J. & Premont, J. (1997). Interleukin-1 enhances the ATP-evoked release of arachidonic acid from mouse astrocytes. J. Neurosci. 17: 939–2946.Google Scholar
  115. Stewart, J., Mitchell, J., & Kalant, N. (1989). The effects of life-long food restriction on spatial memory in young and aged Fischer 344 rats measured in the eight-arm radial and the Morris water mazes. Neurobiol Aging 10: 669–675.PubMedGoogle Scholar
  116. Tokumaru, S., Iguchi, H. & Kojo, S. (1996). Change of the lipid hydroperoxide level in mouse organs on ageing. Mech Ageing Dev 86: 67–74.PubMedGoogle Scholar
  117. Umegaki, K., Hashimoto, M., Yamasaki, H., Fujii, Y., Yoshimura, M., Sugisawa, A. & Shinozuka, K. (2001). Docosahexaenoic acid supplementation-increased oxidative damage in bone marrow DNA in aged rats and its relation to antioxidant vitamins. Free Radic Res 34: 427–35.PubMedGoogle Scholar
  118. Wadsworth, T. L., McDonald, T. L. & Koop, D. R. (2001). Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor-alpha. Biochem Pharmacol 62: 963–74.PubMedGoogle Scholar
  119. Wakimoto, P. & Block, G. (2001). Dietary intake, dietary patterns, and changes with age: an epidemiological perspective. J Gerontol A Biol Sci Med Sci 56 Spec No 2: 65–80.Google Scholar
  120. Wang, H., Cao, G. & Prior, R. L. (1996). Total antioxidant capacity of fruits. J. Agric. Food Chem. 44: 701–705.Google Scholar
  121. Wardle, J. (1988). Cognitive control of eating. J Psychosom Res 32: 607–12.PubMedGoogle Scholar
  122. Winter, E. (1991). Effects of an extract of Ginkgo biloba on learning and memory in mice. Pharmacol Biochem Behav 38: 109–14.PubMedGoogle Scholar
  123. Winter, J. C. (1998). The effects of an extract of Ginkgo biloba, EGb 761, on cognitive behavior and longevity in the rat. Physiol Behav 63: 425–33.PubMedGoogle Scholar
  124. Woodroofe, M. N. (1995). Cytokine production in the central nervous system. Neurol. 45: S6–S10.Google Scholar
  125. Xia, E., Rao, G., Van Remmen, H., Heydari, A. R. & Richardson, A. (1995). Activities of antioxidant enzymes in various tissues of male Fischer 344 rats are altered by food restriction. J Nutr 125: 195–201.PubMedGoogle Scholar
  126. Yao, Z., Drieu, K. & Papadopoulos, V. (2001). The Ginkgo biloba extract EGb 761 rescues the PC 12 neuronal cells from beta-amyloid-induced cell death by inhibiting the formation of beta- amyloid-derived diffusible neurotoxic ligands. Brain Res 889: 181–90.PubMedGoogle Scholar
  127. Youdim, K. A., Shukitt-Hale B., Martin A., Wang H., Denisova N., Bickford P.C. & Joesph, J. A. (2000). Short-tern dietary supplementation of blueberry polyphenolics: beneficial effects on aging brain performance and peripheral tissue function. Nutritional Neuroscience. In Press.Google Scholar
  128. Youdim, K. A. & Joseph, J.A. (2001). A Possible Emerging Role of Phytochemicals in Improving Age-related Neurological Dysfunctions: A Multiplicity of Effects. Free Radial Biology and Medicine In Press.Google Scholar
  129. Zafra, F., Alcantara, R., Gomeza, J., Aragon, C. & Gimenez, C. (1990). Arachidonic acid inhibits glycine transport in cultured glial cells. Biochem J 271: 237–42.PubMedGoogle Scholar
  130. Zafra, M. F., Fernandez-Becerra, M., Castillo, M., Burgos, C. & Garcia-Peregrin, E. (1991). Hypolipidemic activity of dipyridamole: effects on the main regulatory enzyme of cholesterogenesis. Life Sci 49: 15–21.PubMedGoogle Scholar
  131. Zatsepina, O. G., Evgen’ev, M. B. & Liashchko, V. N. (1990). [Changes in the transcription activity of c-myc genes and heat shock proteins (HSP 70) after incubation of mouse plasmacytoma cells with dexamethasone]. Mol Biol (Mosk) 24: 391–5.Google Scholar
  132. Zhang, J. R., Andrus, P. K. & Hall, E. D. (1993). Age-related regional changes in hydroxyl radical stress and antioxidants in gerbil brain. J. Neurochem. 61: 1640–1647.PubMedGoogle Scholar
  133. Zhou, L. J., Song, W., Zhu, X. Z., Chen, Z. L., Yin, M. L., & Cheng, X. F. (2000). Protective effects of bilobalide on amyloid beta-peptide 25-35-induced PC12 cell cytotoxicity. Acta Pharmacol Sin 21: 75–79.PubMedGoogle Scholar
  134. Zhu, H., Guo, Q., Mattson, M.P. (1999). Dietary restriction protects hippocampal neurons against the death-promoting action of a presenilin-1 mutation. Brain Res 842:224–229.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Gemma Casadesus
    • 1
  • Barbara Shukitt-Hale
    • 1
  • Mark A. Smith
    • 2
  • Heather M. Stellwagen
    • 3
  • James A. Joseph
    • 1
  1. 1.USDA-ARS, Human Nutrition Research Center on Aging at Tufts UniversityBostonUSA
  2. 2.Institute of PathologyCase Western Reserve UniversityClevelandUSA
  3. 3.Department of PsychologySimmons CollegeBostonUSA

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