AGE

, Volume 35, Issue 1, pp 23–33 | Cite as

A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice

  • Vadim Aksenov
  • Jiangang Long
  • Jiankang Liu
  • Henry Szechtman
  • Parul Khanna
  • Sarthak Matravadia
  • C. David Rollo
Article

Abstract

We developed a complex dietary supplement designed to offset five key mechanisms of aging and tested its effectiveness in ameliorating age-related cognitive decline using a visually cued Morris water maze test. All younger mice (<1 year old) learned the task well. However, older untreated mice (>1 year) were unable to learn the maze even after 5 days, indicative of strong cognitive decline at older ages. In contrast, no cognitive decline was evident in older supplemented mice, even when ∼2 years old. Supplemented older mice were nearly 50% better at locating the platform than age-matched controls. Brain weights of supplemented mice were significantly greater than controls, even at younger ages. Reversal of cognitive decline in activity of complexes III and IV by supplementation was significantly associated with cognitive improvement, implicating energy supply as one possible mechanism. These results represent proof of principle that complex dietary supplements can provide powerful benefits for cognitive function and brain aging.

Keywords

Cognitive aging Learning Aging Dietary supplements Mitochondria Brain mass 

References

  1. Adlard PA, Perreau VM, Pop V, Cotman CW (2005) Voluntary exercise decreases amyloid load in transgenic model of Alzheimer’s disease. J Neurosci 25:4217–4221PubMedCrossRefGoogle Scholar
  2. Aksenov V, Long J, Lokuge S, Foster JA, Liu J, Rollo CD (2010) A dietary supplement ameliorates locomotor, neurotransmitter and mitochondrial aging. Exp Biol Med 335:66–76Google Scholar
  3. Albers DS, Beal MF (2000) Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease. J Neural Transm Suppl 59:133–154PubMedGoogle Scholar
  4. Allen JS, Bruss J, Brown CK, Damasio H (2005) Normal neuroanatomical variation due to age: the major lobes and a parcellation of the temporal region. Neurobiol Aging 26:1245–1260PubMedCrossRefGoogle Scholar
  5. Alzheimer’s Association (2010) Alzheimer’s disease facts and figures. Alzheimers Dement 6:1–70CrossRefGoogle Scholar
  6. Andreasen NC, Flaum M, Swayze V, O’Leary DS, Alliger R, Cohen G, Ehrhardt J, Yuh NT (1993) Intelligence and brain structure in normal individuals. Am J Psychiatry 150:130–134PubMedGoogle Scholar
  7. Apostolova LG, Thompson PM (2007) Brain mapping as a tool to study neurodegeneration. Neurotherapeutics 4:387–40059PubMedCrossRefGoogle Scholar
  8. Ashe KH, Zahs KR (2010) Probing the biology of Alzheimer’s disease in mice. Neuron 66:631–645PubMedCrossRefGoogle Scholar
  9. Atamna H, Killilea DW, Killilea AN, Ames BN (2002) Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging. PNAS 99:14807–14812PubMedCrossRefGoogle Scholar
  10. Barzilai N, Atzmon G, Derby CA, Bauman JM, Lipton RB (2006) A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology 67:2170–2175PubMedCrossRefGoogle Scholar
  11. Brandies R, Brandies Y, Yehuda S (1989) The use of the Morris water maze in the study of memory and learning. Int J Neurosci 48:29–69CrossRefGoogle Scholar
  12. Carney JM, Starke-Reed PE, Oliver CN, Landum RW, Cheng MS, Wu JF, Floyd RA (1991) Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-α-phenylnitrone. PNAS 88:3633–3636PubMedCrossRefGoogle Scholar
  13. Chandra RK (2001) Effect of vitamin and trace-element supplementation on cognitive function in elderly subjects. Nutrition 17:709–712PubMedCrossRefGoogle Scholar
  14. Chaudhry AM, Marsh-Rollo SE, Aksenov V, Rollo CD, Szechtman H (2008) Modifier selection by transgenes: the case of growth hormone transgenesis and hyperactive circling mice. Evol Biol 35:267–286CrossRefGoogle Scholar
  15. Chen P, Ratcliff G, Belle SH, Cauley JA, DeKosky ST, Ganguli M (2001) Patterns of cognitive decline in presymptomatic Alzheimer disease. Arch Gen Psychiatry 58:853–858PubMedCrossRefGoogle Scholar
  16. Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ (2004) Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem 278:36027–36031CrossRefGoogle Scholar
  17. Cole GM, Frautschy SA (2010) DHA may prevent age-related dementia. J Nutr 140:869–874PubMedCrossRefGoogle Scholar
  18. Crawley JN, Belknap JK, Collins A et al (1997) Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology 132:107–124PubMedCrossRefGoogle Scholar
  19. Creasey H, Rapoport SI (1985) The aging human brain. Ann Neurol 17:2–10PubMedCrossRefGoogle Scholar
  20. Ding Q, Vaynman S, Akhavan M, Ying Z, Gomez-Pinilla F (2006) Insulin-like growth factor I interfaces with brain-derived neurotrophic factor-mediated synaptic plasticity to modulate aspects of exercise-induced cognitive function. Neuroscience 140:823–833PubMedCrossRefGoogle Scholar
  21. Dröge W, Schipper HM (2007) Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell 6:361–370PubMedCrossRefGoogle Scholar
  22. Dubois B, Pillon B (1997) Cognitive deficits in Parkinson’s disease. J Neurol 244:2–8PubMedCrossRefGoogle Scholar
  23. Eilander A, Gera T, Sachdev HS, Transler C, van der Knaap HC, Kok FJ, Osendarp SJ (2010) Multiple micronutrient supplementation for improving cognitive performance in children: systematic review of randomized controlled trials. Am J Clin Nutr 91:115–130PubMedCrossRefGoogle Scholar
  24. Esposito E, Rotilio D, Di Matteo V, Di Giulio C, Cacchio M, Algeri A (2002) A review of specific dietary antioxidants and the effects on biochemical mechanisms related to neurodegenerative processes. Neurobiol Aging 23:719–735PubMedCrossRefGoogle Scholar
  25. Foster TC (1999) Involvement of hippocampal synaptic plasticity in age-related memory decline. Brain Res Rev 30:236–249PubMedCrossRefGoogle Scholar
  26. Gallagher M, Burwell RD (1989) Relationship of age-related decline across several behavioral domains. Neurobiol Aging 10:691–708PubMedCrossRefGoogle Scholar
  27. Gallagher M, Nicolle M (1993) Animal models of normal aging: relationship between cognitive decline and markers in hippocampal circuitry. Behav Brain Res 57:155–162PubMedCrossRefGoogle Scholar
  28. Gomez-Pinilla F (2008) Brain foods: the effects of nutrients on brain function. Nat Rev Neurosci 9:568–578PubMedCrossRefGoogle Scholar
  29. Grossi D, Fasanaro AM, Cecere R, Salzano S, Trojano L (2007) Progressive topographical disorientation: a case of focal Alzheimer’s disease. Neurol Sci 28:107–110PubMedCrossRefGoogle Scholar
  30. Grundman M, Denaney P (2002) Antioxidant strategies for Alzheimer’s disease. Proc Nutr Soc 61:191–202PubMedCrossRefGoogle Scholar
  31. Gu Y, Nieves JW, Stern Y, Luchsinger JA, Scarmeas N (2010) Diet and prevention of Alzheimer disease. JAMA 303:2519–2520CrossRefGoogle Scholar
  32. Herman BH, Nagy ZM (1977) Development of learning and memory in mice genetically selected for differences in brain weight. Dev Psychol 10:65–75Google Scholar
  33. Herring A, Yasin H, Ambrée O, Sachser N, Paulus W, Keyvani K (2008) Environmental enrichment counteracts Alzheimer’s neurovascular dysfunction in TgCRND8 mice. Brain Pathol 18:32–39PubMedCrossRefGoogle Scholar
  34. Hodges JR (2006) Alzheimer’s centennial legacy: origins, landmarks and the current status of knowledge concerning cognitive aspects. Brain 129:2811–2822PubMedCrossRefGoogle Scholar
  35. Holmquist L, Stuchbury G, Berbaum K et al (2007) Lipoic acid as a novel treatment for Alzheimer’s disease and related dementias. Pharmacol Ther 113:154–164PubMedCrossRefGoogle Scholar
  36. Jack CR Jr, Petersen RC, Xu Y et al (1998) Rate of medial temporal lobe atrophy in typical aging and Alzheimer’s disease. Neurology 51:993–999PubMedCrossRefGoogle Scholar
  37. Jack CR Jr, Petersen RC, Xu Y et al (2000) Rates of hippocampal atrophy correlate with change in clinical status in aging and AD. Neurology 55:484–489PubMedCrossRefGoogle Scholar
  38. Jack CR Jr, Shiung MM, Gunter JL et al (2004) Comparison of different MRI brain atrophy rate measures with clinical disease progression in AD. Neurology 62:591–600PubMedCrossRefGoogle Scholar
  39. Jankowski JL, Melnikova T, Fadale DJ et al (2005) Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer’s disease. J Neurosci 25:5217–5224CrossRefGoogle Scholar
  40. Janus C (2004) Search strategies used by APP transgenic mice during navigation in the Morris water maze. Learn Mem 11:337–346PubMedCrossRefGoogle Scholar
  41. Joseph AJ, Shukitt-Hale B, Willis LM (2009) Grape juice, berries and walnuts affect brain aging and behavior. J Nutr 139:1813S–1817SPubMedCrossRefGoogle Scholar
  42. Kausler DH (1994) Learning and memory in normal aging. Academic, San DiegoGoogle Scholar
  43. Kehoe PG, Wilcock GK (2007) Is inhibition of the renin–angiotensin system a new treatment option for Alzheimer’s disease? Lancet Neurol 6:373–378PubMedCrossRefGoogle Scholar
  44. Klapdor K, van der Stay FJ (1996) The Morris water-escape task in mice: strain differences and effects of intra-maze contrast and brightness. Physiol Behav 60:1247–1254PubMedCrossRefGoogle Scholar
  45. Kogan JH, Frankland PW, Blendy JA, Coblentz J, Marowitz Z, Schütz G, Silva AJ (1996) Spaced training induces normal long-term memory in CREB mutant mice. Curr Biol 7:1–11CrossRefGoogle Scholar
  46. Kramer AF, Erickson KI, Colcombe SJ (2006) Exercise, cognition and the aging brain. J Appl Physiol 101:1237–1242PubMedCrossRefGoogle Scholar
  47. Lee YS, Silva AJ (2009) The molecular and cellular biology of enhanced cognition. Nat Rev Neurosci 10:126–140PubMedCrossRefGoogle Scholar
  48. Lemon JA, Boreham DR, Rollo CD (2003) A dietary supplement abolishes age-related cognitive decline in transgenic mice expressing elevated free radical processes. Exp Biol Med 228:800–810Google Scholar
  49. Lemon JA, Boreham DR, Rollo CD (2005) A complex dietary supplement extends longevity of mice. J Gerontol 60A:275–279Google Scholar
  50. Lemon JA, Rollo CD, Boreham DR (2008a) Elevated DNA damage in a mouse model of oxidative stress: impacts of ionizing radiation and a protective dietary supplement. Mutagenesis 23:473–482PubMedCrossRefGoogle Scholar
  51. Lemon JA, Rollo CD, McFarlane NM, Boreham DR (2008b) Radiation-induced apoptosis in mouse lymphocytes is modified by a complex dietary supplement: the effect of genotype and gender. Mutagenesis 23:465–472PubMedCrossRefGoogle Scholar
  52. Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795PubMedCrossRefGoogle Scholar
  53. Long J, Gao F, Tong L, Cotman CW, Ames BN, Liu J (2009) Mitochondrial decay in the brains of old rats: ameliorating effect of alpha-lipoic acid and acetyl-L-carnitine. Neurochem Res 34:755–763PubMedCrossRefGoogle Scholar
  54. Luques L, Shoham S, Weinstock M (2007) Chronic brain cytochrome oxidase inhibition selectively alters hippocampal cholinergic innervation and impairs memory: prevention by ladostigil. Exp Neurol 206:209–219PubMedCrossRefGoogle Scholar
  55. Moffat SD (2009) Aging and spatial navigation: what do we know and where do we go? Neuropsychol Rev 19:478–489PubMedCrossRefGoogle Scholar
  56. Muller FL, Liu Y, Van Remmen H (2004) Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 279:49064–49073PubMedCrossRefGoogle Scholar
  57. Murphy DGM, DeCarli C, Schapiro MB, Rapoport SI, Horwitz B (1992) Age-related differences in volumes of subcortical nuclei, brain matter, and cerebrospinal fluid in healthy men as measured with magnetic resonance imaging. Arch Neurol 49:839–845PubMedCrossRefGoogle Scholar
  58. Navarro A, Boveris A (2007) The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 292:C670–C686PubMedCrossRefGoogle Scholar
  59. Navarro A, Boveris A (2009) Brain mitochondrial dysfunction and oxidative damage in Parkinson’s disease. J Bioenerg Biomembr 41:517–521PubMedCrossRefGoogle Scholar
  60. Nicolle MM, Gonzalez J, Sugaya K et al (2001) Signatures of hippocampal oxidative stress in aged spatial learning-impaired rodents. Neuroscience 107:415–431PubMedCrossRefGoogle Scholar
  61. Osendarp SJ, the NEMO Study Group (2007) Effect of a 12-mo micronutrient intervention on learning and memory in well-nourished and marginally nourished school-aged children: 2 parallel, randomized, placebo-controlled studies in Australia and Indonesia. Am J Clin Nutr 86:1082–1093PubMedGoogle Scholar
  62. Patil SS, Sunyer B, Hoger H, Lubec G (2009) Evaluation of spatial memory of C57BL/6J and CD1 mice in the Barnes maze, the multiple T-maze and in the Morris water maze. Behav Brain Res 198:58–68PubMedCrossRefGoogle Scholar
  63. Pocernich CB, Bader Lange ML, Sultana R, Butterfield DA (2011) Nutritional approaches to modulate oxidative stress in Alzheimer’s disease. Curr Alzh Res 8:452–469CrossRefGoogle Scholar
  64. Relkin NR, Szabo P, Adamiac B et al (2009) 18-month study of intravenous immunoglobulin for treatment of mild Alzheimer’s disease. Neurobiol Aging 30:1728–1736PubMedCrossRefGoogle Scholar
  65. Rollo CD (2009) Dopamine and aging: intersecting facets. Neurochem Res 34:601–629PubMedCrossRefGoogle Scholar
  66. Rollo CD, Ko CV, Tyerman JGA, Kajiura L (1999) The growth hormone axis and cognition: empirical results and integrated theory derived from giant transgenic mice. Can J Zool 77:1874–1890Google Scholar
  67. Scahill RI, Frost C, Jenkins R et al (2003) A longitudinal study of brain volume changes in normal aging using serial registered magnetic resonance imaging. Arch Neurol 60:989–994PubMedCrossRefGoogle Scholar
  68. Scheltens P, Kamphuis PJ, Verhey FR et al (2010) Efficacy of a medical food in mild Alzheimer’s disease: a randomized, controlled trial. Alzheimers Dement 6:1–10e.1PubMedCrossRefGoogle Scholar
  69. Shukitt-Hale B, Lau FC, Joseph JA (2008) Berry fruit supplementation and the aging brain. J Agric Food Chem 56:636–641PubMedCrossRefGoogle Scholar
  70. Sparks DL, Sabbagh MN, Connor DJ et al (2005) Atorvastatin for the treatment of mild to moderate Alzheimer’s disease. Arch Neurol 62:753–757PubMedCrossRefGoogle Scholar
  71. Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858PubMedCrossRefGoogle Scholar
  72. Wehner JM, Silva A (1996) Importance of strain differences in evaluations of learning and memory processes in null mutants. MRDD Res Rev 2:243–248Google Scholar
  73. Widmann CN, Beinhoff U, Riepe MW (2011) Everyday memory deficits in very mild Alzheimer’s disease. Neurobiol Aging. doi:10.1016/j.neurobiolaging2010.03.012
  74. Zahs KR, Ashe KH (2010) ‘Too much good news’—are Alzheimer mouse models trying to tell us how to prevent, not cure, Alzheimer’s disease? Trends Neurosci 33:381–389PubMedCrossRefGoogle Scholar

Copyright information

© American Aging Association 2011

Authors and Affiliations

  • Vadim Aksenov
    • 1
  • Jiangang Long
    • 2
  • Jiankang Liu
    • 2
  • Henry Szechtman
    • 3
  • Parul Khanna
    • 1
  • Sarthak Matravadia
    • 1
  • C. David Rollo
    • 1
  1. 1.Department of BiologyMcMaster UniversityHamiltonCanada
  2. 2.Department of Biology and Engineering, Institute of Mitochondrial Biology and Medicine, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and TechnologyXi’an Jiaotong UniversityXi’anChina
  3. 3.Department of Psychiatry & Behavioural NeurosciencesMcMaster UniversityHamiltonCanada

Personalised recommendations