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



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.

Fig. 1
Fig. 2
Fig. 3


  1. 1.

    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

    CAS  Article  Google Scholar 

  2. 2.

    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

    CAS  Google Scholar 

  3. 3.

    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

    Google Scholar 

  4. 4.

    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

    CAS  Article  Google Scholar 

  5. 5.

    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

    Google Scholar 

  6. 6.

    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

    Article  Google Scholar 

  7. 7.

    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

    CAS  Article  Google Scholar 

  8. 8.

    Farr SA, Price TO et al (2011) Extra virgin olive oil improves learning and memory in SAMP8 mice. J Alzheimers Dis 28:81–92

    Google Scholar 

  9. 9.

    Grossi C, Rigacci S et al (2013) The polyphenol oleuropein aglycone protects TgCRND8 mice against Ass plaque pathology. PLoS One 8:e71702

    CAS  Article  Google Scholar 

  10. 10.

    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

    CAS  Article  Google Scholar 

  11. 11.

    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

    CAS  Article  Google Scholar 

  12. 12.

    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

    CAS  Article  Google Scholar 

  13. 13.

    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

    CAS  Article  Google Scholar 

  14. 14.

    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

    CAS  Article  Google Scholar 

  15. 15.

    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

    CAS  Article  Google Scholar 

  16. 16.

    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

    CAS  Article  Google Scholar 

  17. 17.

    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

    CAS  Article  Google Scholar 

  18. 18.

    Li X, Khanna A et al (2011) Circulatory miR34a as an RNAbased, noninvasive biomarker for brain aging. Aging (Albany NY) 3:985–1002

    CAS  Article  Google Scholar 

  19. 19.

    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

    CAS  Article  Google Scholar 

  20. 20.

    Liu N, Landreh M et al (2012) The microRNA miR-34 modulates ageing and neurodegeneration in Drosophila. Nature 482:519–523

    CAS  Article  Google Scholar 

  21. 21.

    Zovoilis A, Agbemenyah HY et al (2011) microRNA-34c is a novel target to treat dementias. EMBO J 30:4299–4308

    CAS  Article  Google Scholar 

  22. 22.

    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

    CAS  Article  Google Scholar 

  23. 23.

    Eisen MB, Spellman PT et al (1998) Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 95:14863–14868

    CAS  Article  Google Scholar 

  24. 24.

    Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108

    CAS  Article  Google Scholar 

  25. 25.

    Dimmeler S, Nicotera P (2013) MicroRNAs in age-related diseases. EMBO Mol Med 5:180–190

    CAS  Article  Google Scholar 

  26. 26.

    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

    CAS  Google Scholar 

  27. 27.

    Lu T, Pan Y et al (2004) Gene regulation and DNA damage in the ageing human brain. Nature 429:883–891

    CAS  Article  Google Scholar 

  28. 28.

    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

    CAS  Article  Google Scholar 

  29. 29.

    Heinonen AM, Rahman M et al (2014) Neuroprotection by rAAV-mediated gene transfer of bone morphogenic protein 7. BMC Neurosci 15:38

    Article  Google Scholar 

  30. 30.

    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

    CAS  Google Scholar 

  31. 31.

    Nonaka M, Kim R et al (2014) Region-specific activation of CRTC1-CREB signaling mediates long-term fear memory. Neuron 84:92–106

    CAS  Article  Google Scholar 

  32. 32.

    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

    CAS  Article  Google Scholar 

  33. 33.

    Sestan N, Artavanis-Tsakonas S et al (1999) Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science 286:741–746

    CAS  Article  Google Scholar 

  34. 34.

    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

    CAS  Article  Google Scholar 

  35. 35.

    Alberi L, Hoey SE et al (2013) Notch signaling in the brain: in good and bad times. Ageing Res Rev 12:801–814

    CAS  Article  Google Scholar 

  36. 36.

    Costa RM, Honjo T et al (2003) Learning and memory deficits in Notch mutant mice. Curr Biol 13:1348–1354

    CAS  Article  Google Scholar 

  37. 37.

    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

    CAS  Article  Google Scholar 

  38. 38.

    Cocco S, Diaz G et al (2002) Vitamin A deficiency produces spatial learning and memory impairment in rats. Neuroscience 115:475–482

    CAS  Article  Google Scholar 

  39. 39.

    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

    CAS  Article  Google Scholar 

  40. 40.

    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

    Article  Google Scholar 

  41. 41.

    Gingras J, Rassadi S et al (2007) Synaptic transmission is impaired at neuronal autonomic synapses in agrin-null mice. Dev Neurobiol 67:521–534

    CAS  Article  Google Scholar 

  42. 42.

    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

    CAS  Article  Google Scholar 

  43. 43.

    Rimer M (2011) Emerging roles for MAP kinases in agrin signaling. Commun Integr Biol 4:143–146

    CAS  Article  Google Scholar 

  44. 44.

    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

    CAS  Article  Google Scholar 

  45. 45.

    Murai KK, Pasquale EB (2011) Eph receptors and ephrins in neuron-astrocyte communication at synapses. Glia 59:1567–1578

    Article  Google Scholar 

  46. 46.

    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

    CAS  Google Scholar 

  47. 47.

    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

    CAS  Google Scholar 

  48. 48.

    Jiang T, Yu JT et al (2013) beta-Arrestins as potential therapeutic targets for Alzheimer’s disease. Mol Neurobiol 48:812–818

    CAS  Article  Google Scholar 

  49. 49.

    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

    Article  Google Scholar 

  50. 50.

    Olde Loohuis NF, Kos A et al (2012) MicroRNA networks direct neuronal development and plasticity. Cell Mol Life Sci 69:89–102

    CAS  Article  Google Scholar 

  51. 51.

    Salta E, De Strooper B (2012) Non-coding RNAs with essential roles in neurodegenerative disorders. Lancet Neurol 11:189–200

    CAS  Article  Google Scholar 

  52. 52.

    Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233

    CAS  Article  Google Scholar 

  53. 53.

    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

    CAS  Article  Google Scholar 

  54. 54.

    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

    CAS  Article  Google Scholar 

  55. 55.

    Eda A, Takahashi M et al (2011) Alteration of microRNA expression in the process of mouse brain growth. Gene 485:46–52

    CAS  Article  Google Scholar 

  56. 56.

    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

    Article  Google Scholar 

  57. 57.

    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

    CAS  Article  Google Scholar 

  58. 58.

    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

    CAS  Article  Google Scholar 

  59. 59.

    Blade C, Baselga-Escudero L et al (2013) miRNAs, polyphenols, and chronic disease. Mol Nutr Food Res 57:58–70

    CAS  Article  Google Scholar 

  60. 60.

    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

    CAS  Article  Google Scholar 

  61. 61.

    Arola-Arnal A, Blade C (2011) Proanthocyanidins modulate microRNA expression in human HepG2 cells. PLoS One 6:e25982

    CAS  Article  Google Scholar 

  62. 62.

    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

    CAS  Article  Google Scholar 

Download references


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.

Author information



Corresponding author

Correspondence to Cristina Luceri.

Ethics declarations

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.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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

Download citation


  • Aging brain
  • miRNomics
  • Genomics
  • Phenolic compounds
  • Nutraceuticals