Skip to main content

Advertisement

Log in

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

AGE Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Adlard PA, Perreau VM, Pop V, Cotman CW (2005) Voluntary exercise decreases amyloid load in transgenic model of Alzheimer’s disease. J Neurosci 25:4217–4221

    Article  PubMed  CAS  Google Scholar 

  • 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 335:66–76

    Google Scholar 

  • Albers DS, Beal MF (2000) Mitochondrial dysfunction and oxidative stress in aging and neurodegenerative disease. J Neural Transm Suppl 59:133–154

    PubMed  CAS  Google Scholar 

  • 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 26:1245–1260

    Article  PubMed  Google Scholar 

  • Alzheimer’s Association (2010) Alzheimer’s disease facts and figures. Alzheimers Dement 6:1–70

    Article  Google Scholar 

  • 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 150:130–134

    PubMed  CAS  Google Scholar 

  • Apostolova LG, Thompson PM (2007) Brain mapping as a tool to study neurodegeneration. Neurotherapeutics 4:387–40059

    Article  PubMed  Google Scholar 

  • Ashe KH, Zahs KR (2010) Probing the biology of Alzheimer’s disease in mice. Neuron 66:631–645

    Article  PubMed  CAS  Google Scholar 

  • Atamna H, Killilea DW, Killilea AN, Ames BN (2002) Heme deficiency may be a factor in the mitochondrial and neuronal decay of aging. PNAS 99:14807–14812

    Article  PubMed  CAS  Google Scholar 

  • Barzilai N, Atzmon G, Derby CA, Bauman JM, Lipton RB (2006) A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology 67:2170–2175

    Article  PubMed  CAS  Google Scholar 

  • Brandies R, Brandies Y, Yehuda S (1989) The use of the Morris water maze in the study of memory and learning. Int J Neurosci 48:29–69

    Article  Google Scholar 

  • 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 88:3633–3636

    Article  PubMed  CAS  Google Scholar 

  • Chandra RK (2001) Effect of vitamin and trace-element supplementation on cognitive function in elderly subjects. Nutrition 17:709–712

    Article  PubMed  CAS  Google Scholar 

  • 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 35:267–286

    Article  Google Scholar 

  • Chen P, Ratcliff G, Belle SH, Cauley JA, DeKosky ST, Ganguli M (2001) Patterns of cognitive decline in presymptomatic Alzheimer disease. Arch Gen Psychiatry 58:853–858

    Article  PubMed  CAS  Google Scholar 

  • 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 278:36027–36031

    Article  Google Scholar 

  • Cole GM, Frautschy SA (2010) DHA may prevent age-related dementia. J Nutr 140:869–874

    Article  PubMed  CAS  Google Scholar 

  • Crawley JN, Belknap JK, Collins A et al (1997) Behavioral phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology 132:107–124

    Article  PubMed  CAS  Google Scholar 

  • Creasey H, Rapoport SI (1985) The aging human brain. Ann Neurol 17:2–10

    Article  PubMed  CAS  Google Scholar 

  • 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 140:823–833

    Article  PubMed  CAS  Google Scholar 

  • Dröge W, Schipper HM (2007) Oxidative stress and aberrant signaling in aging and cognitive decline. Aging Cell 6:361–370

    Article  PubMed  Google Scholar 

  • Dubois B, Pillon B (1997) Cognitive deficits in Parkinson’s disease. J Neurol 244:2–8

    Article  PubMed  CAS  Google Scholar 

  • 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 91:115–130

    Article  PubMed  CAS  Google Scholar 

  • 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 23:719–735

    Article  PubMed  CAS  Google Scholar 

  • Foster TC (1999) Involvement of hippocampal synaptic plasticity in age-related memory decline. Brain Res Rev 30:236–249

    Article  PubMed  CAS  Google Scholar 

  • Gallagher M, Burwell RD (1989) Relationship of age-related decline across several behavioral domains. Neurobiol Aging 10:691–708

    Article  PubMed  CAS  Google Scholar 

  • Gallagher M, Nicolle M (1993) Animal models of normal aging: relationship between cognitive decline and markers in hippocampal circuitry. Behav Brain Res 57:155–162

    Article  PubMed  CAS  Google Scholar 

  • Gomez-Pinilla F (2008) Brain foods: the effects of nutrients on brain function. Nat Rev Neurosci 9:568–578

    Article  PubMed  CAS  Google Scholar 

  • Grossi D, Fasanaro AM, Cecere R, Salzano S, Trojano L (2007) Progressive topographical disorientation: a case of focal Alzheimer’s disease. Neurol Sci 28:107–110

    Article  PubMed  CAS  Google Scholar 

  • Grundman M, Denaney P (2002) Antioxidant strategies for Alzheimer’s disease. Proc Nutr Soc 61:191–202

    Article  PubMed  CAS  Google Scholar 

  • Gu Y, Nieves JW, Stern Y, Luchsinger JA, Scarmeas N (2010) Diet and prevention of Alzheimer disease. JAMA 303:2519–2520

    Article  CAS  Google Scholar 

  • Herman BH, Nagy ZM (1977) Development of learning and memory in mice genetically selected for differences in brain weight. Dev Psychol 10:65–75

    CAS  Google Scholar 

  • 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 18:32–39

    Article  PubMed  CAS  Google Scholar 

  • Hodges JR (2006) Alzheimer’s centennial legacy: origins, landmarks and the current status of knowledge concerning cognitive aspects. Brain 129:2811–2822

    Article  PubMed  Google Scholar 

  • Holmquist L, Stuchbury G, Berbaum K et al (2007) Lipoic acid as a novel treatment for Alzheimer’s disease and related dementias. Pharmacol Ther 113:154–164

    Article  PubMed  CAS  Google Scholar 

  • Jack CR Jr, Petersen RC, Xu Y et al (1998) Rate of medial temporal lobe atrophy in typical aging and Alzheimer’s disease. Neurology 51:993–999

    Article  PubMed  Google Scholar 

  • 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 55:484–489

    Article  PubMed  Google Scholar 

  • 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 62:591–600

    Article  PubMed  Google Scholar 

  • Jankowski JL, Melnikova T, Fadale DJ et al (2005) Environmental enrichment mitigates cognitive deficits in a mouse model of Alzheimer’s disease. J Neurosci 25:5217–5224

    Article  Google Scholar 

  • Janus C (2004) Search strategies used by APP transgenic mice during navigation in the Morris water maze. Learn Mem 11:337–346

    Article  PubMed  Google Scholar 

  • Joseph AJ, Shukitt-Hale B, Willis LM (2009) Grape juice, berries and walnuts affect brain aging and behavior. J Nutr 139:1813S–1817S

    Article  PubMed  CAS  Google Scholar 

  • Kausler DH (1994) Learning and memory in normal aging. Academic, San Diego

    Google Scholar 

  • Kehoe PG, Wilcock GK (2007) Is inhibition of the renin–angiotensin system a new treatment option for Alzheimer’s disease? Lancet Neurol 6:373–378

    Article  PubMed  CAS  Google Scholar 

  • 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 60:1247–1254

    Article  PubMed  CAS  Google Scholar 

  • 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 7:1–11

    Article  Google Scholar 

  • Kramer AF, Erickson KI, Colcombe SJ (2006) Exercise, cognition and the aging brain. J Appl Physiol 101:1237–1242

    Article  PubMed  Google Scholar 

  • Lee YS, Silva AJ (2009) The molecular and cellular biology of enhanced cognition. Nat Rev Neurosci 10:126–140

    Article  PubMed  CAS  Google Scholar 

  • 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 228:800–810

    CAS  Google Scholar 

  • Lemon JA, Boreham DR, Rollo CD (2005) A complex dietary supplement extends longevity of mice. J Gerontol 60A:275–279

    CAS  Google Scholar 

  • 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 23:473–482

    Article  PubMed  CAS  Google Scholar 

  • 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 23:465–472

    Article  PubMed  CAS  Google Scholar 

  • Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    Article  PubMed  CAS  Google Scholar 

  • 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 34:755–763

    Article  PubMed  CAS  Google Scholar 

  • 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 206:209–219

    Article  PubMed  CAS  Google Scholar 

  • Moffat SD (2009) Aging and spatial navigation: what do we know and where do we go? Neuropsychol Rev 19:478–489

    Article  PubMed  Google Scholar 

  • Muller FL, Liu Y, Van Remmen H (2004) Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 279:49064–49073

    Article  PubMed  CAS  Google Scholar 

  • 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 49:839–845

    Article  PubMed  CAS  Google Scholar 

  • Navarro A, Boveris A (2007) The mitochondrial energy transduction system and the aging process. Am J Physiol Cell Physiol 292:C670–C686

    Article  PubMed  CAS  Google Scholar 

  • Navarro A, Boveris A (2009) Brain mitochondrial dysfunction and oxidative damage in Parkinson’s disease. J Bioenerg Biomembr 41:517–521

    Article  PubMed  CAS  Google Scholar 

  • Nicolle MM, Gonzalez J, Sugaya K et al (2001) Signatures of hippocampal oxidative stress in aged spatial learning-impaired rodents. Neuroscience 107:415–431

    Article  PubMed  CAS  Google Scholar 

  • 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 86:1082–1093

    PubMed  CAS  Google Scholar 

  • 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 198:58–68

    Article  PubMed  Google Scholar 

  • Pocernich CB, Bader Lange ML, Sultana R, Butterfield DA (2011) Nutritional approaches to modulate oxidative stress in Alzheimer’s disease. Curr Alzh Res 8:452–469

    Article  CAS  Google Scholar 

  • Relkin NR, Szabo P, Adamiac B et al (2009) 18-month study of intravenous immunoglobulin for treatment of mild Alzheimer’s disease. Neurobiol Aging 30:1728–1736

    Article  PubMed  CAS  Google Scholar 

  • Rollo CD (2009) Dopamine and aging: intersecting facets. Neurochem Res 34:601–629

    Article  PubMed  CAS  Google Scholar 

  • 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 77:1874–1890

    CAS  Google Scholar 

  • 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 60:989–994

    Article  PubMed  Google Scholar 

  • 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.1

    Article  PubMed  CAS  Google Scholar 

  • Shukitt-Hale B, Lau FC, Joseph JA (2008) Berry fruit supplementation and the aging brain. J Agric Food Chem 56:636–641

    Article  PubMed  CAS  Google Scholar 

  • Sparks DL, Sabbagh MN, Connor DJ et al (2005) Atorvastatin for the treatment of mild to moderate Alzheimer’s disease. Arch Neurol 62:753–757

    Article  PubMed  Google Scholar 

  • Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858

    Article  PubMed  Google Scholar 

  • Wehner JM, Silva A (1996) Importance of strain differences in evaluations of learning and memory processes in null mutants. MRDD Res Rev 2:243–248

    Google Scholar 

  • 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

  • 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 33:381–389

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by a grant to CDR from the Natural Sciences and Engineering Research Council of Canada. We thank Zoya Tov for her contributions to diet preparation and technical support for the experiments.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Jiankang Liu or C. David Rollo.

About this article

Cite this article

Aksenov, V., Long, J., Liu, J. et al. A complex dietary supplement augments spatial learning, brain mass, and mitochondrial electron transport chain activity in aging mice. AGE 35, 23–33 (2013). https://doi.org/10.1007/s11357-011-9325-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-011-9325-2

Keywords

Navigation