Middle-aged C57Bl/6J mice fed for 6 months with extra-virgin olive oil rich in phenols (H-EVOO, phenol dose/day: 6 mg/kg) showed cognitive and motor improvement compared to controls fed the same olive oil deprived of phenolics (L-EVOO). The aim of the present study was to evaluate whether these behavioral modifications were associated with changes in gene and miRNA expression in the brain.
Two brain areas involved in cognitive and motor processes were chosen: cortex and cerebellum. Gene and miRNA profiling were analyzed by microarray and correlated with performance in behavioral tests.
After 6 months, most of the gene expression changes were restricted to the cerebral cortex. The genes modulated by aging were mainly down-regulated, and the treatment with H-EVOO was associated with a significant up-regulation of genes compared to L-EVOO. Among those, we found genes previously associated with synaptic plasticity and with motor and cognitive behavior, such as Notch1, BMPs, NGFR, GLP1R and CRTC3. The agrin pathway was also significantly modulated. miRNAs were mostly up-regulated in old L-EVOO animals compared to young. However, H-EVOO-fed mice cortex displayed miRNA expression profiles similar to those observed in young mice. Sixty-three miRNAs, out of 1203 analyzed, were significantly down-regulated compared to the L-EVOO group; among them, we found miRNAs whose predicted target genes were up-regulated by the treatment, such as mir-484, mir-27, mir-137, mir-30, mir-34 and mir-124.
We are among the first to report that a dietary intervention starting from middle age with food rich in phenols can modulate at the central level the expression of genes and miRNAs involved in neuronal function and synaptic plasticity, along with cognitive, motor and emotional behavior.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Buckland G, Mayen AL et al (2012) Olive oil intake and mortality within the Spanish population (EPIC-Spain). Am J Clin Nutr 96:142–149
Valls-Pedret C, Lamuela-Raventos RM et al (2012) Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk. J Alzheimers Dis 29:773–782
Giovannelli L (2013) Beneficial effects of olive oil phenols on the aging process: experimental evidence and possible mechanisms of action. Nutr Aging 1:207–223
Pitt J, Roth W et al (2009) Alzheimer’s-associated Abeta oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal. Toxicol Appl Pharmacol 240:189–197
D’Angelo S, Manna C et al (2001) Pharmacokinetics and metabolism of hydroxytyrosol, a natural antioxidant from olive oil. Drug Metab Dispos 29:1492–1498
Serra A, Rubio L et al (2011) Distribution of olive oil phenolic compounds in rat tissues after administration of a phenolic extract from olive cake. Mol Nutr Food Res 56:486–496
Pitozzi V, Jacomelli M et al (2012) Long-term dietary extra-virgin olive oil rich in polyphenols reverses age-related dysfunctions in motor coordination and contextual memory in mice: role of oxidative stress. Rejuvenation Res 15:601–612
Farr SA, Price TO et al (2011) Extra virgin olive oil improves learning and memory in SAMP8 mice. J Alzheimers Dis 28:81–92
Grossi C, Rigacci S et al (2013) The polyphenol oleuropein aglycone protects TgCRND8 mice against Ass plaque pathology. PLoS One 8:e71702
Bayram B, Ozcelik B et al (2012) A diet rich in olive oil phenolics reduces oxidative stress in the heart of SAMP8 mice by induction of Nrf2-dependent gene expression. Rejuvenation Res 15:71–81
Chang J, Rimando A et al (2012) Low-dose pterostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer’s disease. Neurobiol Aging 33:2062–2071
Park SK, Kim K et al (2009) Gene expression profiling of aging in multiple mouse strains: identification of aging biomarkers and impact of dietary antioxidants. Aging Cell 8:484–495
Abraham J, Johnson RW (2009) Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice. Rejuvenation Res 12:445–453
Castagnini C, Luceri C et al (2009) Reduction of colonic inflammation in HLA-B27 transgenic rats by feeding Marie Menard apples, rich in polyphenols. Br J Nutr 102:1620–1628
Giovannelli L, Pitozzi V et al (2011) Effects of de-alcoholised wines with different polyphenol content on DNA oxidative damage, gene expression of peripheral lymphocytes, and haemorheology: an intervention study in post-menopausal women. Eur J Nutr 50:19–29
Milenkovic D, Deval C et al (2012) Modulation of miRNA expression by dietary polyphenols in apoE deficient mice: a new mechanism of the action of polyphenols. PLoS One 7:e29837
Somel M, Guo S et al (2010) MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain. Genome Res 20:1207–1218
Li X, Khanna A et al (2011) Circulatory miR34a as an RNAbased, noninvasive biomarker for brain aging. Aging (Albany NY) 3:985–1002
Khanna A, Muthusamy S et al (2011) Gain of survival signaling by down-regulation of three key miRNAs in brain of calorie-restricted mice. Aging (Albany NY) 3:223–236
Liu N, Landreh M et al (2012) The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila. Nature 482:519–523
Zovoilis A, Agbemenyah HY et al (2011) microRNA-34c is a novel target to treat dementias. EMBO J 30:4299–4308
Lippi G, Steinert JR et al (2011) Targeting of the Arpc3 actin nucleation factor by miR-29a/b regulates dendritic spine morphology. J Cell Biol 194:889–904
Eisen MB, Spellman PT et al (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95:14863–14868
Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108
Dimmeler S, Nicotera P (2013) MicroRNAs in age-related diseases. EMBO Mol Med 5:180–190
Blalock EM, Chen KC et al (2003) Gene microarrays in hippocampal aging: statistical profiling identifies novel processes correlated with cognitive impairment. J Neurosci 23:3807–3819
Lu T, Pan Y et al (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429:883–891
Chang CF, Lin SZ et al (2003) Intravenous administration of bone morphogenetic protein-7 after ischemia improves motor function in stroke rats. Stroke 34:558–564
Heinonen AM, Rahman M et al (2014) Neuroprotection by rAAV-mediated gene transfer of bone morphogenic protein 7. BMC Neurosci 15:38
Markowska AL, Koliatsos VE et al (1994) Human nerve growth factor improves spatial memory in aged but not in young rats. J Neurosci 14:4815–4824
Nonaka M, Kim R et al (2014) Region-specific activation of CRTC1-CREB signaling mediates long-term fear memory. Neuron 84:92–106
Abbas T, Faivre E et al (2009) Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: interaction between type 2 diabetes and Alzheimer’s disease. Behav Brain Res 205:265–271
Sestan N, Artavanis-Tsakonas S et al (1999) Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science 286:741–746
Hitoshi S, Alexson T et al (2002) Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev 16:846–858
Alberi L, Hoey SE et al (2013) Notch signaling in the brain: in good and bad times. Ageing Res Rev 12:801–814
Costa RM, Honjo T et al (2003) Learning and memory deficits in Notch mutant mice. Curr Biol 13:1348–1354
Jacobs S, Lie DC et al (2006) Retinoic acid is required early during adult neurogenesis in the dentate gyrus. Proc Natl Acad Sci USA 103:3902–3907
Cocco S, Diaz G et al (2002) Vitamin A deficiency produces spatial learning and memory impairment in rats. Neuroscience 115:475–482
Wey MC, Fernandez E et al (2012) Neurodegeneration and motor dysfunction in mice lacking cytosolic and mitochondrial aldehyde dehydrogenases: implications for Parkinson’s disease. PLoS One 7:e31522
Hao PP, Chen YG et al (2011) Meta-analysis of aldehyde dehydrogenase 2 gene polymorphism and Alzheimer’s disease in East Asians. Can J Neurol Sci 38:500–506
Gingras J, Rassadi S et al (2007) Synaptic transmission is impaired at neuronal autonomic synapses in agrin-null mice. Dev Neurobiol 67:521–534
Chiamulera C, Di Chio M et al (2008) Nicotine-induced phosphorylation of phosphorylated cyclic AMP response element-binding protein (pCREB) in hippocampal neurons is potentiated by agrin. Neurosci Lett 442:234–238
Rimer M (2011) Emerging roles for MAP kinases in agrin signaling. Commun Integr Biol 4:143–146
Onodera T, Sakudo A et al (2014) Review of studies that have used knockout mice to assess normal function of prion protein under immunological or pathophysiological stress. Microbiol Immunol 58:361–374
Murai KK, Pasquale EB (2011) Eph receptors and ephrins in neuron-astrocyte communication at synapses. Glia 59:1567–1578
Willi R, Winter C et al (2012) Loss of EphA4 impairs short-term spatial recognition memory performance and locomotor habituation. Genes Brain Behav 11:1020–1031
Li M, Linseman DA et al (2001) Myocyte enhancer factor 2A and 2D undergo phosphorylation and caspase-mediated degradation during apoptosis of rat cerebellar granule neurons. J Neurosci 21:6544–6552
Jiang T, Yu JT et al (2013) beta-Arrestins as potential therapeutic targets for Alzheimer’s disease. Mol Neurobiol 48:812–818
Aksoy-Aksel A, Zampa F et al (2014) MicroRNAs and synaptic plasticity—a mutual relationship. Philos Trans R Soc Lond B Biol Sci 369:20130515
Olde Loohuis NF, Kos A et al (2012) MicroRNA networks direct neuronal development and plasticity. Cell Mol Life Sci 69:89–102
Salta E, De Strooper B (2012) Non-coding RNAs with essential roles in neurodegenerative disorders. Lancet Neurol 11:189–200
Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233
Bates DJ, Liang R et al (2009) The impact of noncoding RNA on the biochemical and molecular mechanisms of aging. Biochim Biophys Acta 1790:970–979
Haramati S, Navon I et al (2011) MicroRNA as repressors of stress-induced anxiety: the case of amygdalar miR-34. J Neurosci 31:14191–14203
Eda A, Takahashi M et al (2011) Alteration of microRNA expression in the process of mouse brain growth. Gene 485:46–52
Li Y, Kong D et al (2010) Regulation of microRNAs by natural agents: an emerging field in chemoprevention and chemotherapy research. Pharm Res 27:1027–1041
Tsang WP, Kwok TT (2010) Epigallocatechin gallate up-regulation of miR-16 and induction of apoptosis in human cancer cells. J Nutr Biochem 21:140–146
Bae S, Lee EM et al (2011) Resveratrol alters microRNA expression profiles in A549 human non-small cell lung cancer cells. Mol Cells 32:243–249
Blade C, Baselga-Escudero L et al (2013) miRNAs, polyphenols, and chronic disease. Mol Nutr Food Res 57:58–70
Baselga-Escudero L, Blade C et al (2012) Grape seed proanthocyanidins repress the hepatic lipid regulators miR-33 and miR-122 in rats. Mol Nutr Food Res 56:1636–1646
Arola-Arnal A, Blade C (2011) Proanthocyanidins modulate microRNA expression in human HepG2 cells. PLoS One 6:e25982
Martinez I, Cazalla D et al (2011) miR-29 and miR-30 regulate B-Myb expression during cellular senescence. Proc Natl Acad Sci USA 108:522–527
The authors thank Prof. Sabrina Giglio and Dr. Marilena Pantaleo for technical support for the scanning of microarray images. The present study was financially supported by the University of Florence and by the Ente Cassa di Risparmio di Firenze. VP at the time of the present experiments was affiliated at the Department of Pharmacology of the University of Florence.
Conflict of interest
Each author has made substantial contributions to the conception and design of the study or acquisition of data or analysis and interpretation of data, drafting the article or revising it critically for important intellectual content. Each author has seen and approved the contents of the submitted manuscript. The authors declare that they have no personal or financial interests.
About this article
Cite this article
Luceri, C., Bigagli, E., Pitozzi, V. et al. A nutrigenomics approach for the study of anti-aging interventions: olive oil phenols and the modulation of gene and microRNA expression profiles in mouse brain. Eur J Nutr 56, 865–877 (2017). https://doi.org/10.1007/s00394-015-1134-4
- Aging brain
- Phenolic compounds