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The multifunctional therapeutic potentiality of extra virgin olive oil administration through the intervention in pathophysiological mechanisms: Focus on Alzheimer's disease


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Proper dietary habits pave the way for a good and healthy life in order to maintain and prolong the quality of life. It is well known that quality of life in the elderly can be achieved by non-pharmacological approaches such as performing physical activity, cognitive training, or adhering to a Mediterranean Diet (MedDiet). The MedDiet is suggested as the prevalent dietary regimen and is strongly correlated with prevention of degenerative diseases and longevity. The most distinguished and beneficial ingredient of MedDiet is extra virgin olive oil (EVOO). Indeed, numerous epidemiological studies have proved that the consumption of olive oil was associated with better overall health. The foremost component of EVOO is polyphenolic compounds which are under investigation for its biological and pharma-nutritional properties. In this review we recorded several representative in vitro and in vivo studies performed in culture cell lines, in animal or clinical trials, indicating that the regular intake of EVOO is associated with enhanced neuroprotective, antioxidant, anti-inflammatory, anti-atherosclerotic, anti-cancer and anti-microbial properties. Furthermore, it is emerged the demand of more randomized controlled or longitudinal observational studies to be performed to confirm the efficacy of the beneficial health effect of EVOO.
Corresponding author: Pantazaki A
Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Makedonia, Greece.
Copyright © 2021 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0.
The multifunctional therapeutic potentiality of extra virgin olive oil administration
through the intervention in pathophysiological mechanisms: Focus on Alzheimer's
Tzekaki E 1, 4, Prodromou S 3, 4, Tsolaki M 2, 3, 4, * and Pantazaki Α A 1, 4, *
1 Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki,
Makedonia, Greece.
2 Department of Neurology, Medical School, “AHEPA” General Hospital Medical School, Aristotle University of
Thessaloniki, Faculty of Health Sciences 54124 Thessaloniki, Makedonia, Greece.
3 Greek Association of Alzheimer's Disease and Related Disorders GAADRD.
4 Center for Interdisciplinary Research and Innovation, Laboratory of Neurodegenerative Diseases (LND), Aristotle
University of Thessaloniki.
GSC Advanced Research and Reviews, 2021, 07(01), 101113
Publication history: Received on 13 March 2021; revised on 16 April 2021; accepted on 19 April 2021
Article DOI:
Proper dietary habits pave the way for a good and healthy life in order to maintain and prolong the quality of life. It is
well known that quality of life in the elderly can be achieved by non-pharmacological approaches such as performing
physical activity, cognitive training, or adhering to a Mediterranean Diet (MedDiet). The MedDiet is suggested as the
prevalent dietary regimen and is strongly correlated with prevention of degenerative diseases and longevity. The most
distinguished and beneficial ingredient of MedDiet is extra virgin olive oil (EVOO). Indeed, numerous epidemiological
studies have proved that the consumption of olive oil was associated with better overall health. The foremost
component of EVOO is polyphenolic compounds which are under investigation for its biological and pharma-nutritional
properties. In this review we recorded several representative in vitro and in vivo studies performed in culture cell lines,
in animal or clinical trials, indicating that the regular intake of EVOO is associated with enhanced neuroprotective,
antioxidant, anti-inflammatory, anti-atherosclerotic, anti-cancer and anti-microbial properties. Furthermore, it is
emerged the demand of more randomized controlled or longitudinal observational studies to be performed to confirm
the efficacy of the beneficial health effect of EVOO.
Keywords: Extra virgin olive oil; Anticancer properties; Antioxidant properties; Anti-inflammatory properties;
Neuroprotective properties
GSC Advanced Research and Reviews, 2021, 07(01), 101113
Graphical abstract
1. Introduction
The term “Mediterranean Diet” (MedDiet) was introduced for the first time by Ancel Keys in the early 1960s in order to
signify an exceptional dietary practice followed by the countries around the Mediterranean basin [1]. The positive
effects of the Mediterranean diet were first proposed in the early 1970s [2]. Fifty (50) years later, numerous studies
confirmed the initial findings and associated with reduced risk of many diseases such as cardiovascular disease (CVD),
stroke, certain types of cancer, diabetes, non-alcoholic liver disease and finally Mild Cognitive Impairment (MCI) and
Alzheimer's disease (AD). Currently, there is not an effective and approved pharmacological agent specific for MCI, and
for this reason it is recommended the use of the non-pharmacological personalized interventions (e.g., cognitive
stimulation, training, etc.) which are also not approved yet.
2. Intrinsic beneficial EVOO properties due to composition
The composition of EVOO is 98% fatty acids (glycerol tri-esters with fatty acids), among which is oleic acid (55-83%)
and 2% other minor ingredients, in lower concentrations such as free fatty acids, phospholipids, polar phenols,
tocopherols, pigments, squalene along with other hydrocarbons, tri-terpenic acids and others [1]. Among functional
foods, one finds the EVOO, an essential food of the MedDiet in countries such as Spain, Italy, and Greece which represent
the most important producers in the world. As documented by numerous studies published in recent decades, most of
the beneficial effects of the MedDiet on promoting human health can be attributed to EVOO [24].
EVOO is regarded as a functional food since epidemiological studies and multidisciplinary research have reported
convincing evidence that its intake beneficially affects one or more targeted functions in the body, improves health, and
reduces the risk of disease [4], [69]. Its properties on health have been related to the major and minor component
fractions of EVOO. The beneficial properties of EVOO have been attributed to its high content of monounsaturated fatty
acids (MUFA), which represent up to 80% of its total lipid composition. However, recent evidence has shown that the
minor components of EVOO, such as phenolic and other compounds with antioxidant actions, determine an increase in
the health characteristics of the oil itself [9, 10].
Among the EVOO chemical components, the phenolic fraction has received considerable attention due to its bioactivity
in different chronic diseases. Polar phenolic compounds are a family of compounds found in fruits, vegetables, wine, tea,
and in a variety of oils including virgin olive oil. EVOO contain different classes of phenolic compounds such as phenyl
alcohols, hydroxytyrosol (HT) and tyrosol, quinic/hydroxycinnamic acids (caffeic and p-coumaric acid) and benzoic acid
(vanillic acid), flavones (apigenin and luteolin), secoiridoids oleuropein (OLE), and ligstroside derivatives [11]. This
class of compounds is inextricably linked to the stability of oils as they exhibit strong antioxidant activity by binding
various reactive oxygen species (ROS). Additionally, apart from the MUFA and the phenolic compounds the nutritional
and antioxidant properties of EVOO are related to the presence and content of tocopherols and carotenoids which are
of grave importance for human health [12]. Table 1 showed the content in minor components of virgin olive oil and
refined one.
GSC Advanced Research and Reviews, 2021, 07(01), 101113
Table 1 Content in minor components of extra virgin olive oil and refined one.
Minor components
Extra Virgin Olive
Oil (mg/kg)
Refined Extra Virgin
Olive Oil (mg/kg)
Volatile Esters
Volatile carbonyl
Tri-terpenic Alcohols
Aliphatic Alcohols
EVOO contains oleic acid approximately 0.8 grams/100 grams and peroxides less than 20 milli-equivalents of oxygen
which are referred as free acidity and they formed by extraction of olive fruits. The production of olive oil must take
place by mechanical means without solvents and under 30oC for avoiding the degradation. The MUFA which are
contained in EVOO- principal role have oleic acid- are known for their potential to reduce low-density lipoprotein
cholesterol (LDL-C) levels. The bioactivity of the phenolic compounds could be related to different properties such as
anti-inflammatory and antioxidant ones, although the molecular action mechanism of these compounds in relation to
many diseases might have different cellular targets or may be multimodal /or pleotropic [1]. Diet rich in fruits and
vegetables contributes to a better life-span, to the longevity and to the diminution of the inflammation and oxidative
stress risk associated with chronic diseases (e.g., CVD, arteriosclerosis, cancer, diabetes, cataract, disorders of the
cognitive function, and neurological diseases) [13]. The high concentration of EVOO in polyphenols seems to have anti-
inflammatory and antioxidant properties [14] and oleocanthal (OC) in particular exerts an anti-inflammatory action
similar to ibuprofen [15, 16].
EVOO itself is rich in vitamins D, A, E and helps the absorption of the whole group of fat - soluble vitamins. EVOO, rich
in polyphenols, is able to reduce heterocyclic amines and plasma levels of C-reactive protein [17]. Therefore, the positive
impact of EVOO on human health could be attributed to a synergistic effect of polyphenolic compounds, the high content
of oleic acid, and the content in vitamins D, A, E. The components contained in olive oil are summarized in Fig.1.
Figure 1 Components contained in olive oil
GSC Advanced Research and Reviews, 2021, 07(01), 101113
3. Biological activities of EVOO
The favorable outcomes of EVOO consumption is broadly known and accepted. For this reason, the European Food
Safety Authority (EFSA) [Commission Regulation (EU) 432/2012] has adopted two health approvals [18]. First, EVOO
is highly recommended to be used to supersede saturated fats for maintenance of normal blood cholesterol levels [5].
Second, EFSA declares that EVOO’s antioxidant protection of blood lipids from oxidative stress is due thanks to the
polyphenols which are dominant in a human daily intake of 20 g of EVOO. This claim is only referred to EVOO containing
at least 5 mg of HT and its derivatives per 20 g of OO [5].
An increasing tendency of meta-analyses results prove a refinement on morbidity and mortality’s levels, cardiovascular
problems (e.g. stroke, hypertension), neurodegenerative disorders, types of cancer and metabolic diseases such as type
II diabetes thanks to olive oil consumption [3,1921]. One of the greatest public health challenges worldwide is the
obesity pandemic. Studies support that the use of virgin olive oil as the sole culinary fat lessened the body mass index
but long-term trials are needed for confirmation [3]. Studies focusing on CVD suggest that virgin olive oil reduce blood
pressure and also has anti-atherosclerotic potential [3].
The above-mentioned ingredients contained in olive oil exert an anti-oxidant potential against the conglomeration of
reactive oxygen and nitrogen species steering to changes in redox signaling and molecular damage [22]. Free radicals
formed by an unpaired electron on oxidants or on nitric oxide (NO) exert destructive effects on lipids, DNA molecules,
and proteins. Moreover, the excessive oxidant compounds are inextricably linked to the onset of CVD,
neurodegenerative diseases, and cancer undoubtedly [23].
Specifically, tau protein which is a microtubule-associated protein that promotes microtubule assembly and stability is
fibrillated and aggregated into neurofibrillary tangles in AD and related taupathies. OC abolished fibrillization of tau by
locking tau into the naturally unfolded state [24, 25].
OC has also a non-steroidal anti-inflammatory potential as ibuprofen has [24]. OLE, another dominant constituent of
olive oil is proved to have anti-inflammatory activity [26] and antioxidant activity [5]. Studies showed beneficial
outcomes in decrease of coronary atherosclerosis and control blood pressure [27] and it was also explored for its
antitumor activity [28].
3.1. Experiments in cells culture
EVOO or OLE treatment alone may act as a natural PAI-1 (Plasminogen activator inhibitor 1) inhibitor by incrementally
destabilizing PAI-1 protein levels selectively in estrogen receptor (ER) and progesterone receptor (PR) negative [ER-
/PR-] breast cancer cells, accompanied by cell growth inhibition. In contrast, ER+/PR+ breast cancer cells where PAI-1
expression is absent or low, do not adequately respond to this treatment [7].
It is proposed that HT, a major polyphenol found in olive oil, completely scavenges free radicals in vitro and exerting
cytoprotection potential against oxidative stress-induced damage in PC12 cells. HT completely protects the cells from
hydrogen peroxide-induced death [29].
Moreover, OLE significantly increased the cleaved PARP [Poly (ADP-Ribose) Polymerase 1] levels in MCF-7 human
breast cancer cells in a dose-dependent mechanism, increasing apoptotic cascade by preventing the activation of PARP
[30], and further promote the expression of a significant level of cleaved PARP1 after 48 h treatment of melanoma cells
with OLE [31]. DNA damage is the primary activator of the enzyme PARP-1 that catalyzes the reaction of poly (ADP-
ribosylation), a post-translational modification of proteins involved in many physiological processes, such as gene
expression, maintenance of genomic stability, and cell death [32].
The significance of these outcomes may become understanding taken into consideration that a PARP-1 inhibitor,
olaparib, is the first-in-class PARP-1 inhibitor marketed in 2014 as monotherapy for advanced BRCA-deficient ovarian
cancer. Breast cancer is a social burden and the most frequent cancer in women and the first cause of death by cancer
in women. Approximately 23% of all breast cancer cases are due to germline mutations in either the BRCA1 or BRCA2
(BRCA1/2) gene. These kinds of mutations have the highest identifiable life-time risk of developing breast cancer.
BRCA1/2 mutation carries lack of expression and/or function of the corresponding protein, which induces genomic
instability [33].
In addition, a series of new olaparib derivatives were designed and synthesized as multifunctional PARP-1 and
cholinesterase inhibitors acting as neuroprotectors [3437], to treat AD, an upshot that may be assured with the
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consumption of a natural product as EVOO. Moreover, OLE induces apoptosis in SKBR3 breast cancer cells activating
the mitochondrial apoptotic pathway, which leads to cleavage of PARP-1 and caspase-9, and caspase-3, also [38, 39]. HT
decreases PARP-1 protein levels and its activity in MCF-7 breast cancer cells [34]. Moreover, OC inhibited colony
formation and induced apoptosis, as confirmed by PARP cleavage, activation of caspases 3/7, and chromatin
condensation in colon cancer cells [40].
An olive secoiridoid, possesses powerful antioxidant and anti-inflammatory activities, which suggests its potential
application to treat neuroinflammatory disorders. Oleacein-treated multiple myeloma cell line induced the increase in
cleaved PARP1, caspase-3 and caspase-8 leading to apoptosis induction [36].
Increased levels of the enzyme iNOS generate augmented levels of NO in conjunction with ROS and other neurotoxic
factors that steer to neuronal death [37, 41]. Pretreatment of ATDC-5 cells with OC significantly inhibited the bacterial
lipopolysaccharide-induced NO production in a dose-dependent manner in a murine chondrocyte cell line [42]. In
lipopolysaccharide-stimulated murine peritoneal macrophage isolated cells, OC was able to downregulate iNOS
inhibiting its protein expression [43]. The in vitro study by Palmieri et al. (2012) clearly revealed that the incubation of
human endothelial cells (AEhy926) with OLE (10, 20 and 50 µg/mL) under anoxia stress resulted in significant decrease
in the level of NO and the expression of iNOS [44].
The effects of OO phenolic extract and individual compounds were investigated on MMP-9 in THP-1 cells, a
human monocyte-like cell line [45], due to impaired nuclear factor-κB signaling providing further evidence on the
mechanisms by which olive oil reduces the inflammatory burden associated with disorders, such as atherosclerosis.
Table 2 shows representative significant biological effects of bioactive phenolic compounds of virgin olive oil.
Table 2 Significant biological effects of bioactive phenolic compounds of virgin olive oil.
Effectiveness against Alzheimer’s disease
Reduction of oxidative stress
[5], [8], [35]
Improving root stability
ROS commitment
Inhibition of LDL oxidation
Inhibition of DNA oxidation
Reduction of GSSG
Increase GSH
[36], [37]
Reduction of cytokines’ levels
Decrease of myocardial injury
ROS commitment
Antiproliferative action
Induction of apoptosis
Anti-immigration action
Inhibition of angiogenesis
Reduction of steatosis
Antimicrobial action of cell membrane
[9], [45]
3.2. Experiments in animals
Studies carried out in rats proved that EVOO administration lessened the inflammatory levels with a concomitant
refinement of serum antioxidant potential [46]. In vitro screening tests of OO containing biophenols at 800 mg/kg of OO
was supplemented for 14 days to male Wistar rats at a dose corresponding to 20 g OO/per day to humans. The results
reinforced the antioxidant capacity which OO exerts at blood, brain, muscle and intestines’ levels [5].
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OLE is characterized by antibacterial [47] and antiviral activity [48]. OLE induced reduction of Poly(ADP-Ribose)
Polymerase 1 (PARP-1) activation, concluding that OLE treatment counteracts neuronal damage through modulation of
the PARP1-SIRT1 interplay in the TgCRND8 mouse model [49]. OLE was also found to inhibit the inducible nitric oxide
synthase (iNOS) expression in rats [50], reviewed about [51], in mice [52], having a neuroprotective role and anti-
inflammatory effect in mice [53].
Cerebral infarction is a common cerebrovascular disease throughout the world having high rates of mortality and
disability, and it overrunning society [54]. Having born in mind that intravenous thrombolysis therapy is effective but
many patients fail to receive the treatment in time [55]. Yu et al. 2016 proved the neuroprotective effect exert from OLE
on cerebral ischemia and reperfusion injury in a middle cerebral artery occlusion model in mice in a dose-dependent
manner. OLE is a lipophilic molecule with small molecular weight and can cross the blood-brain barrier (BBB) when the
BBB is broken during cerebral ischemic injury [56]. Treatment with OLE is proposed to reduce cerebral infarct volume
and provides neuroprotection in focal cerebral ischemia/reperfusion injury in mice [56]. Researchers declare for its
safety and indeed there is yet to find the lethal dose when used an elevated dose (1 g/kg body weight) of OLE in albino
mice [57]. The use of OLE lessened myocardial injury in rats caused by an acute myocardial infarction through the
resistance of oxidative stress and anti-inflammatory activity, as anti-inflammation is a major cause of apoptosis [58, 59].
Neuroprotective effect in spinal cord injury in rats proposed by the use of OLE [60]. OLE supplementation in rats
ameliorates oxidative tissue damage by scavenging free radicals [61]. Beneficial results and robust anti-oxidant activity
showed in short-term feeding rats with olive oil [5]. Treatment of elderly rats with OLE through oral gavage reduced
oxidative damage in the substantia nigra pars compacta molded by increasing antioxidant enzyme activity [62].
Additionally, OLE ameliorates the oxidative/nitrosative stress and suppresses inflammation and improved histological
and plasma markers of liver damage in carbon tetrachloride (CCl4)-induced liver injury in male BALB/cN mice [53]. In
a rat model of TBI (trauma brain injury) it was proved that the production of eNOS and iNOS were significantly
decreased with OC treatment in a dose-dependent manner [63] indicating that OC has a protective potential on neural
cells after TBI by decreasing the oxidative stress in plasma, and apoptosis [63].
TgSwDI mice fed with EVOO demonstrated a great benefit in hallmarks of AD- the tau protein, and amyloid-β-. EVOO-
enriched diet for a duration of 6 months restored the levels of Aβ and tau protein in the brain, accompanied by improved
cognitive behavior; suggesting that the long-term consumption of EVOO, starting at an early age, provides a protective
effect to fight AD [64].
As is also the case for short term transgenic tau mice (hTau) models [65] and long-term feeding with EVOO aged rats
and C57B1/6J mice which made headway in biochemical parameters, improved memory, and motor coordination
thanks to antioxidant phenols of olive oil which reduce the unbalanced levels of oxidative stress in ageing rats and in
mice respectively [66,67]. Transgenic SwDI mice, expressing human amyloid β precursor protein (APP) after enriched
EVOO diet, showed decreased total brain Aβ accompanied by cognitive improvement. Mice, which were diagnosed with
Aβ aggregation, after three-month EVOO consumption, diminished this symptom. It is possible that EVOO reduced the
brain’s Aβ by enforcing the Aβ clearance across the BBB and by lowering Aβ production via a modulated process of APP
in the brains of TgSwDI mice [64,68].
3.3. Experiment in humans
Studies carried out in humans proposed that the EVOO consumption containing high and/or moderate bio-phenolic
ingredients protects LDL from oxidation and increases the levels of HDL cholesterol entailing a dose-dependent
attenuation of oxidative stress [8, 69]. It is also known the protection of DNA strands from oxidative damage and the
decrease of cancer development [70]. In the frame of a clinical trial which deals with EVOO administration in MCI
patients it was demonstrated restoration of DNA damage and PARP-1 attenuation which correlates with reduction of
oxidative stress (unpublished data).
А decreased risk of dementia has been strongly related to the direct effect of MedDiet components on the metabolism
of AD hallmarks [71, 72]; a substantial part of those positive effects has been attributed to EVOO consumption [4, 73].
In this field studies in elderly shed light to the risk of the onset of dementia thanks to the high intake of EVOO and
polyphenols [7476], exhibiting a significantly positive impact on cognitive function.
Cognitive performance has been associated with dietary habits and, in parallel, cognitive decline and neurodegenerative
disorders have been related to oxidative stress. We could hypothesize that reducing oxidative stress through the
consumption of antioxidant-rich foods could protect people from neurodegenerative diseases. Previous research has
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confirmed that participants who intensely consumed EVOO exhibited a decrease in cognitive decline in a 4-year
timeline, in contrast to those whose intake of EVOO was rare or zero [77].
The clinical trial MICOIL [78] very recently demonstrated significant improvement in ADAS-cog (p=0.001) and MMSE
(p=0.05) in groups of patients after one year intervention received EVOO and mainly independent of the presence of
APOE ε4, whereas the non-consuming group displayed worse or similar to baseline performance in almost all domains.
In detail, consuming groups had better outcomes in respect with ADAS-cog (p=0.003), Digit Span (p=0.006), and Letter
fluency (p=0.003).
As a continuation of the clinical trial MICOIL [78], the biochemical study of Tzekaki et al. [79] was to investigate one of
the possible different pathways involved in the AD onset and on disease progression and evaluate the beneficial effect
of the annual EVOO administration in MCI patients, not only in neuropsychological tests but in AD biomarkers and
biochemical pioneers actors of biochemical pathways in order to support, strengthen and confirm the clinical trial, and
prove consistency. Cascades of events correlated with inflammatory responses and oxidative stress may activate a
mechanism of some pathological events. Synaptic dysfunction and neurodegeneration in the brain is a result of events
happening in the intra-cellular level. Biomarkers for Amyloid β (Aβ) plaque, neurofibrillary tangles, and brain atrophy
serve as the limited window on biology available to the clinician. The biomarkers field is already vast, there is a growing
demand to predict, diagnose, and to targeted fight the generative causes of AD for reversing them, and especially
through natural approaches.
Taken into consideration the already known beneficial properties of EVOO including neuroprotective, antioxidant, anti-
inflammatory, anticoagulant, anti-microbial [65,68,71,72,77,78,8086] we toured and gleaned determinant factors of
various biochemical pathways which may be altered by the EVOO intervention, and accessible to be measured in serum
of MCI patients.
In this frame, we focused on the effect of the annual EVOO consumption on factors of the fibrinolytic system, and
especially on the principal one PAI-1, (which already has been reported as an AD biomarker), on a2-antiplasmin, and
moreover on the tPA protease. Really, one of the main mechanisms in which EVOO is implicated was in the annulation
of PAI-1 activity. As a result, we found increased tissue plasminogen activator (tPA) and a2-antiplasmin activity which
reflected augmented Aβ fragments’ degradation [79]. A malfunction of the tPA-plasmin system causes defective
proteolytic degradation of plaques in advanced stages of AD [87]. Soluble Aβ-induced synaptic dysfunction is an
untimely event in the pathogenesis of AD that precedes the deposition of insoluble Aβ and correlates with the evolution
of cognitive deficits rather than with the number of plaques [87]. The already known EVOO’s antioxidant properties
were demonstrated to intervene in AD prevention in this trial by implication in the oxidative stress quenching by
measurement of the lipid peroxidation characteristic biomarker, the malondialdehyde [6].
Figure 2 Model depicting the properties of EVOO administration on different pathways exerting its neuroprotective,
anti-coagulant, anti-oxidant and anti-inflammatory effect on health defence.
A second scientific query was directed towards the effect of EVOO on neuroprotective proteins and focused on the B
lymphoma Mo-MLV insertion region 1 (Bmi1) levels. BMI-1 is mechanistically required to repress Microtubule
Associated Protein Tau (MAPT) transcription and hinder p53 stabilization, thereby preventing neurodegeneration.
Increased BMI-1 levels activate the neuroprotective cascade which correlated with diminution of p53 levels. Moreover,
p53-mediated activity moderates the induced neuronal apoptosis through the quantified decreased levels of caspase-8
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[88]. Encouraging outcomes were that the annual administration of EVOO in MCI patients reinstated the BMI-1 levels in
their sera, and restored the levels of the hallmarks AD biomarkers’, confirming again the EVOO beneficial effect realized
through another pathway [6]. The results of our study are summarized in an illustrator of Fig. 2.
Neuro-inflammatory processes are a central feature of ΑD in which microglia are over-activated, resulting in the
increased production of pro-inflammatory cytokines [89]. Inflammation is a devastating factor accused of the onset of
neurodegeneration and interleukin-6 (IL-6) - inflammatory cytokine - increases in AD brain due to Aβ conglomeration.
Reports proved that augmented IL-6 was found in old and BMI1-/- brains, as BMI-1 deficiency reflects in p53 hyper
activation, which in turn augments IL-6 levels resulting in aging and neurodegeneration [90]. Thanks to the EVOO anti-
inflammatory properties the IL-6 in conjunction with TNF-α levels were found decreases in sera of MCI patients treated
with EVOO annually [6]. A schematic approach which is embodied BMI1-involvement in mechanistic pathway entailing
to Alzheimer’s disease onset it is summarized in Fig. 3.
Figure 3 Cascade of reactions in AD pathology and involvement of EVOO administration.
All the above-mentioned cascades of events end up in the conglomeration of Αβ oligomers, and neurofibrillary tangles.
Previous research showed that reduction of Aβ1-42 and Aβ1-40 plasma levels were associated with cognitive decline,
indicating AD’s clinical symptoms [91]. EVOO enriched-diet reversed the hallmarks of AD such as increased p-tau and
Aβ species accumulation as quantified in MCI patients’ sera. Our concept based on that the driving force and the key
that correlates and simultaneously activates these pathways lies in the accumulation of oxidative stress and free
radicals, which in turn, the senescent brain fails to clear. Our findings may imply that a natural product which is
characterized broadly with antioxidant and anti-inflammatory potential may halt the progression of MCI to AD.
4. Highlights
This review deals with the impact of EVOO dedication on the underlying mechanisms reported previously.
Oral intake of Extra Virgin Olive Oil has beneficial effect in many diseases and focus on AD
Provides a record of experiments in cell lines, animal clinical trials studies
This meta-analysis involved data from many articles
5. Conclusion
There is no doubt about the beneficial effects of MedDiet on public health. MedDiet is strongly correlated with high
consumption of EVOO the most characterized ingredient of it. The beneficial effects of olive oil and its biomolecules on
GSC Advanced Research and Reviews, 2021, 07(01), 101113
neurological disorders have been extensively investigated from the perspective of different cell pathways. The
protective effect of EVOO as a whole and of its components separately is proved against LDL oxidation and oxidative
stress, steaming from brain to lessen the inflammatory levels after spinal cord injury (in animal model), and to overcome
the hurdle of amyloid deposition (in vitro and in animal models) and to delay the cognitive decline among non-demented
older individuals. In conclusion, further investigation in a bigger cohort of human patients is demanded for acquiring
warranties certifying this treasure as a natural and alternative, less toxic therapy for numerous disorders worldwide.
MedDiet, Mediterranean Diet; EVOO, Extra Virgin Olive Oil; CVD, cardiovascular disease; MCI, Mild Cognitive
Impairment; AD, Alzheimer's disease; MUFA, monounsaturated fatty acids; HT, hydroxytyrosol; ROS, reactive oxygen
species; NO, nitric oxide; OC, oleocanthal; OLE, Oleuropein; PAI-1, Plasminogen activator inhibitor 1; ER, Estrogen
receptor; PR, progesterone receptor; PARP1, Poly(ADP-Ribose) Polymerase 1; BCA1, Breast cancer type 1 susceptibility
protein; iNOS, Inducible nitric oxide synthase, intracellular nitric oxide synthase; MMP-9, metalloproteinase 9; BBB,
blood-brain barrier; TBI, traumatic brain injury; tPA, tissue plasminogen activator, BMI1, B lymphoma Mo-MLV
insertion region 1 homolog; MAPT, Microtubule-associated protein tau.
Compliance with ethical standards
This work was funded by Alzheimer Hellas, Thessaloniki, Greece and Yanni’s Olive Grove Company providing the Early
Harvest EVOO and EVOO, Potidea Chalkidiki, Greece.
Disclosure of conflict of interest
The authors declare that they have no conflict of interest.
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... A substantial part of those positive effects has been attributed to EVOO consumption (Foscolou et al., 2018;Serra-Majem et al., 2004). The multifunctional therapeutic capability of EVOO consumption through the intervention in pathophysiological mechanisms including AD is recently reviewed (Tzekaki et al., 2021a). ...
... Western blotting for detection of PARP-1 in sera was carried out as previously described (Tzekaki et al., 2021a), and signal intensity was assessed via alkaline phosphatase staining according to previously published protocols (Tzekaki et al., 2021b). The following primary antibodies were employed at a concentration of 1:1000: β-actin (sc-130300); 1:500: PARP-1 (sc-74470). ...
... EVOO, dominant component of Mediterranean diet, has been shown to reduce the potential of cognitive decline dependent on the aging process. All the favorable outcomes of EVOO consumption in clinical trials, animal models and cell cultures are reviewed (Tzekaki et al., 2021a). ...
Oxidative/nitrative stress that results from the unbalance of the overproduction/clearance of reactive oxygen/nitrogen species (ROS/NOS), originated from a variety of endo- and/or exo-genous sources, can have detrimental effects on DNA and is involved in Alzheimer's disease (AD) pathology. An excellent marker of oxidative DNA lesions is 8-hydroxy-2′-deoxyguanosine (8-OHdG) while of nitrative stress the enzyme NOS2 (Nitric oxide synthase 2). Under massive oxidative stress, poly(ADP-ribose)polymerase 1 (PARP-1) enzyme activity, responsible for restoration of DNA damage, is augmented, DNA repair enzymes are recruited, and cell survival/or death is ensued through PARP-1 activation, which is correlated positively with neurodegenerative diseases. In this biochemical study the levels of PARP-1, 8-oxo-dG, and NOS2, Aβ1–42, and p-tau in their sera determined using Enzyme-Linked Immunosorbent Assay (ELISA). Patients diagnosed with Mild Cognitive Impairment participated in MICOIL clinical trial, were daily administered with 50 ml Extra Virgin Olive Oil (EVOO) for one year. All MCI patients' biomarkers that had consumed EVOO were tantamount to those of healthy participants, contrary to MCI patients who were not administered. EVOO administration in MCI patients resulted in the restoration of DNA damage and of the well-established “hallmarks” AD biomarkers, thanks probably to its antioxidant properties exhibiting a therapeutic potentiality against AD. Molecular docking simulations of the EVOO constituents on the crystal structure of PARP-1 and NOS-2 target enzymes were also employed, to study in silico the ability of the compounds to bind to these enzymes and explain the observed in vitro activity. In silico analysis has proved the binding of EVOO constituents on PARP-1and NOS-2 enzymes and their interaction with crucial amino acids of the active sites. Clinical trial registration MICOIL gov identifier NCT03362996.
... The participants were given either early harvest extra virgin olive oil (EHEVOO), Medi+ EHEVOO, or only Medi. After 12 months, the Medi+ EHEVOO group experienced better cognitive abilities compared to Medi alone, especially in general cognition, attention, and fluency tasks, independently of the presence of the APOEε4 gene (8,9). Vassilopoulou et al., using a confirmatory factor analysis, examined the dietary components of the MIND diet among Greek elderly populations. ...
... MD is considered as a highly antioxidant and anti-inflammatory diet due to the richness of phytochemicals originated from different MD ingredients, all acting in synergy and having antioxidant and anti-inflammatory effects. The frequently-found nutrients in MD are given in Figure 2. Emphasis on polyphenolic compounds and their classification along with the chemical structures of some of the representatives of each class are also given in Figure 2 [14][15][16][17][94][95][96][97][98][99][100][101][102][103][104][105][106]. ...
Attractive for its palatability and unique flavourful food choices, the Mediterranean Diet (MD) is one of the most studied dietary patterns due to its numerous health and well-being benefits. MD is, also, an example of a sustainable food system and lifestyle that can be easily implemented outside the Mediterranean basin. It is mainly a plant-based diet, which emphasizes abundant consumption of unprocessed or minimally processed fruits, vegetables, whole grains, nuts, legumes, seeds, herbs and spices, followed by moderate consumption of fish, poultry, eggs and low-fat dairy and fermented dairy products. Extra Virgin Olive Oil (EVOO), the cornerstone of the MD, is the main source of healthy fats, while the consumption of red meat products and products with refined sugars is low. Plenty of fluids like water, juices, herb teas, coffees, and soups are frequently consumed to maintain a good hydration, as well as red wine consumed in moderation with the meals is practiced in some of the Mediterranean countries depending on the culture, traditions and religious beliefs. An updated MD food pyramid describing the main ingredients of this dietary pattern is proposed. The phytonutrients, consumed daily within the MD and acting in synergy, are responsible for the highly antioxidant and antiinflammatory nature of this diet and are briefly described.
Extra Virgin Olive Oil (EVOO) symbolises the prominently cherished Mediterranean food. It is typically a lipidic source within the cookery of the Mediterranean nations, and its intake has been correlated to decreased illness and reduced disease progressions. This review attempts to summarise the empirical evidence concerning the state-of-the-art and illuminate the most crucial point of view concerning future research needs on the prospective therapeutic benefits of EVOO potential health benefits and bioavailability. Therefore, Web of Science, Scopus, and other Databases were queried using some predefined criteria. The literature search was limited to studies published from 2007 to 2022. Subsequently, fifty-three (53) studies were chosen and analysed. These studies present EVOOs analyses and their potential health benefits and bioavailability. Results revealed that fifteen (15) studies (28.3%) have some evaluation concerning the benefits of phenolic compounds. Anti-inflammatory potentials of EVOO were reported by 9.4% of the reviewed articles. Antioxidant-related analysis, Secoiridoids, and Fatty acids constituted 5.7%, respectively. These were followed by antimicrobial activity/antibacterial, polyphenols, healing of human intestinal infection, functional ingredients extraction to develop an essential food blend, and analysis of dynamics and membrane composition, which constituted 3.8%, respectively. The remaining descriptive faces constituted 2% of the reviewed literature. Results further revealed that despite the vast established literature concerning the therapeutic importance of chemical compounds found in extra virgin olive oil and their relationship to biological indicators, there is still a need for further evaluations of the less-reported aspects of EVOO's health benefits. Therefore, the current and future reviews have to be analysed within the context of existing state-of-the-art knowledge concerning EVOO's therapeutic benefits to human health and regular standard application of accepted field, laboratory, milling and storage standards in the literature.
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Background: Extra virgin olive oil (EVOO) constitutes a natural compound with high protection over cognitive function. Objective: To investigate for the first time the effect of Greek High Phenolic Early Harvest Extra Virgin Olive Oil (HP-EH-EVOO) versus Moderate Phenolic (MP-EVOO) and Mediterranean Diet (MeDi) in people with mild cognitive impairment (MCI). Methods: We conducted a randomized prospective study so as to examine the HP-EH-EVOO and MP-EVOO versus MeDi in MCI. Genetic predisposition (APOEɛ4) to Alzheimer's disease (AD) was tested and an extensive neuropsychological battery was administered at baseline and after 12 months. Each participant was randomized and assigned one of three groups: 1) Group 1 received the HP-EH-EVOO (50 mL/day); 2) Group 2 received the MP-EVOO (50 mL/day), and 3) Group 3 received only the MeDi instructions. Results: Better follow-up performance was found in Group 1 compared to Group 2 and Group 3 in the almost all cognitive domains. Moreover, Group 2 showed also significant improvement compared to Group 3 in ADAS-cog (p = 0.001) and MMSE (p = 0.05), whereas Group 3 exhibited worse or similar to baseline performance in almost all domains. In particular, Group 1 and Group 2 had better outcomes with regards to ADAS-cog (p = 0.003), Digit Span (p = 0.006), and Letter fluency (p = 0.003). Moreover, there was a significant difference (p = 0.001) in the presence of APOEɛ4 between the Groups 1 and 2 versus Group 3. Conclusion: Long-term intervention with HP-EH-EVOO or MP-EVOO was associated with significant improvement in cognitive function compared to MeDi, independent of the presence of APOEɛ4.
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Soluble amyloid β (Aβ)-induced synaptic dysfunction is an early event in the pathogenesis of Alzheimer's disease (AD) that precedes the deposition of insoluble Aβ and correlates with the development of cognitive deficits better than the number of plaques. The mammalian plasminogen activation (PA) system catalyzes the generation of plasmin via two activators: tissue-type (tPA) and urokinase-type (uPA). A dysfunctional tPA-plasmin system causes defective proteolytic degradation of Aβ plaques in advanced stages of AD. In contrast, it is unknown if uPA and its receptor (uPAR) contribute to the pathogenesis of this disease. Neuronal cadherin (NCAD) plays a pivotal role in the formation of synapses and dendritic branches, and Aβ decreases its expression in cerebral cortical neurons. Here we show that neuronal uPA protects the synapse from the harmful effects of soluble Aβ. However, Aβ-induced inactivation of the eukaryotic initiation factor 2α (eIF2α) halts the transcription of uPA mRNA, leaving unopposed the deleterious effects of Aβ on the synapse. In line with these observations, the synaptic abundance of uPA but not uPAR is decreased in the frontal cortex of AD patients and 5xFAD mice, and in cerebral cortical neurons incubated with soluble Aβ. We found that uPA-treatment increases the synaptic expression of NCAD by a uPAR-mediated plasmin-independent mechanism, and that uPA-induced formation of NCAD dimers protects the synapse from the harmful effects of soluble Aβ oligomers. These data indicate that Aβ-induced decrease in the synaptic abundance of uPA contributes to the development of synaptic damage in the early stages of AD.Significance statementSoluble Aβ-induced synaptic dysfunction is an early event in the pathogenesis of cognitive deficits in AD. We found that neuronal uPA protects the synapse from the deleterious effects of soluble Aβ. However, Aβ-induced inactivation of the eIF2α decreases the synaptic abundance of uPA, leaving unopposed the harmful effects of Aβ on the synapse. In line with these observations, the synaptic expression of uPA is decreased in the frontal cortex of AD brains and 5xFAD mice, and uPA-treatment abrogates the deleterious effects of Aβ on the synapse. These results unveil a novel mechanism of Aβ-induced synaptic dysfunction in AD patients, and indicate that recombinant uPA is a potential therapeutic strategy to protect the synapse before the development of irreversible brain damage.
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Olive oil intake has been linked with a lower incidence of breast cancer. Hypoxic microenvironment in solid tumors, such as breast cancer, is known to play a crucial role in cancer progression and in the failure of anticancer treatments. HIF-1 is the foremost effector in hypoxic response, and given that hydroxytyrosol (HT) is one of the main bioactive compounds in olive oil, in this study we deepen into its modulatory role on HIF-1. Our results in MCF-7 breast cancer cells demonstrate that HT decreases HIF-1α protein, probably by downregulating oxidative stress and by inhibiting the PI3K/Akt/mTOR pathway. Strikingly, the expression of HIF-1 target genes does not show a parallel decrease. Particularly, adrenomedullin and vascular endothelial growth factor are up-regulated by high concentrations of HT even in HIF-1α silenced cells, pointing to HIF-1-independent mechanisms of regulation. In fact, we show, by in silico modelling and transcriptional analysis, that high doses of HT may act as an agonist of the aryl hydrocarbon receptor favoring the induction of these angiogenic genes. In conclusion, we suggest that the effect of HT in a hypoxic environment is largely affected by its concentration and involves both HIF-1 dependent and independent mechanisms.
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In recent years, increasing evidence has accumulated supporting the health benefits of extra virgin olive oil (EVOO). Previous studies showed that EVOO supplementation improves Alzheimer's disease (AD)‐like amyloidotic phenotype of transgenic mice. However, while much attention has been focused on EVOO‐mediated modulation of Aβ processing, its direct influence on tau metabolism in vivo and synaptic function is still poorly characterized. In this study, we investigated the effect of chronic supplementation of EVOO on the phenotype of a relevant mouse model of tauopathy, human transgenic tau mice (hTau). Starting at 6 months of age, hTau mice were fed chow diet supplemented with EVOO or vehicle for additional 6 months, and then the effect on their phenotype was assessed. At the end of the treatment, compared with control mice receiving EVOO displayed improved memory and cognition which was associated with increased basal synaptic activity and short‐term plasticity. This effect was accompanied by an upregulation of complexin 1, a key presynaptic protein. Moreover, EVOO treatment resulted in a significant reduction of tau oligomers and phosphorylated tau at specific epitopes. Our findings demonstrate that EVOO directly improves synaptic activity, short‐term plasticity, and memory while decreasing tau neuropathology in the hTau mice. These results strengthen the healthy benefits of EVOO and further support the therapeutic potential of this natural product not only for AD but also for primary tauopathies. Chronic administration of extra‐virgin olive oil increases synaptic activity and short‐term plasticity, improves memory, and reduces tau neuropathology.
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Currently, there is an increase in the number of the world's aging population. This aging process is often connected with cognitive decline of some functions such as memory or speed processing loss. Since Alzheimer's disease cannot be cured yet, considerable efforts are being made to at least delay this cognitive decline among elderly in order to maintain and prolong the quality of their life. This can also be achieved by non-pharmacological approaches such as performing physical activities, cognitive training, or adhering to a Mediterranean Diet (MedDiet). One of the components of MedDiet - extra-virgin olive oil (EVOO) - has considerable health benefits. The purpose of this review is to examine the effect of EVOO intake on the delay of cognitive decline among the elderly. The methodology is based on a literature review of available sources found on the research topic in three acknowledged databases: Web of Science, Scopus, and PubMed. The results of in vitro and in vivo studies indicate that the regular intake of EVOO is associated with enhanced cognitive functions, which means that this oil may have a neuroprotective effect and could positively prevent the development of dementia, especially Alzheimer's dementia. It is believed that secoiridoid oleuropein is responsible for this effectiveness. Furthermore, there is also a need of more randomized controlled studies or longitudinal observational studies to be performed to confirm the efficacy of the beneficial health effect of EVOO on the delay of cognitive decline.
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The Mediterranean diet is considered as the foremost dietary regimen and its adoption is associated with the prevention of degenerative diseases and an extended longevity. The preeminent features of the Mediterranean diet have been agreed upon and the consumption of olive oil stands out as the most peculiar one. Indeed, the use of olive oil as the nearly exclusive dietary fat is what mostly characterizes the Mediterranean area. Plenty of epidemiological studies have correlated that the consumption of olive oil was associated with better overall health. Indeed, extra virgin olive oil contains (poly)phenolic compounds that are being actively investigated for their purported biological and pharma-nutritional properties. On 18 and 19 May 2018, several experts convened in Jaen (Spain) to discuss the most recent research on the benefits of olive oil and its components. We reported a summary of that meeting (reviewing several topics related to olive oil, not limited to health) and concluded that substantial evidence is accruing to support the widespread opinion that extra virgin olive oil should, indeed, be the fat of choice when it comes to human health and sustainable agronomy.
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Olive oil contains different biologically active polyphenols, among which oleacein, the most abundant secoiridoid, has recently emerged for its beneficial properties in various disease contexts. By using in vitro models of human multiple myeloma (MM), we here investigated the anti-tumor potential of oleacein and the underlying bio-molecular sequelae. Within a low micromolar range, oleacein reduced the viability of MM primary samples and cell lines even in the presence of bone marrow stromal cells (BMSCs), while sparing healthy peripheral blood mononuclear cells. We also demonstrated that oleacein inhibited MM cell clonogenicity, prompted cell cycle blockade and triggered apoptosis. We evaluated the epigenetic impact of oleacein on MM cells, and observed dose-dependent accumulation of both acetylated histones and α-tubulin, along with down-regulation of several class I/II histone deacetylases (HDACs) both at the mRNA and protein level, providing evidence of the HDAC inhibitory activity of this compound; conversely, no effect on global DNA methylation was found. Mechanistically, HDACs inhibition by oleacein was associated with down-regulation of Sp1, the major transactivator of HDACs promoter, via Caspase 8 activation. Of potential translational significance, oleacein synergistically enhanced the in vitro anti-MM activity of the proteasome inhibitor carfilzomib. Altogether, these results indicate that oleacein is endowed with HDAC inhibitory properties, which associate with significant anti-MM activity both as single agent or in combination with carfilzomib. These findings may pave the way to novel potential anti-MM epi-therapeutic approaches based on natural agents.
The daily consumption of Extra Virgin Olive Oil (EVOO) in Mediterranean nutrition is tightly associated with lower frequency of many diseases' appearance, including Alzheimer's disease (AD). Fibrinolytic system is already assumed to be involved in AD pathophysiology through various factors, especially plasminogen activator inhibitor-1 (PAI-1), a2-antiplasmin (α2ΑP) and tissue plasminogen activator (tPA). We, here, present a biochemical study, as a continuation of a clinical trial of a cohort of 84 participants, focusing on the pleiotropic effect of the annual EVOO consumption on the fibrinolytic factors of Mild Cognitive Impairment (MCI) patients. The levels of all these fibrinolytic factors, measured by Enzyme-Linked Immunosorbent Assay (ELISA) method, were reduced in the serum of MCI patients annually administered with EVOO, versus not treated MCI patients, as well as AD patients. The well-established AD hallmarks (Aβ1–40 and Aβ1–42 species, tau, and p-tau) of MCI patients' group, annually administered with EVOO, were restored to levels equal to those of the cognitively-healthy group; in contrast to those patients not being administered, and their AD hallmarks levels increased at the end of the year. Moreover, one of the EVOO annual consumption multimodal effects on the MCI patients focused on the levels of an oxidative stress trademark, malondialdehyde (MDA), which displayed also a visible quenching; On the other hand, an increase exhibited in the MCI patients not consuming EVOO one year after, was attributed to the lack of the EVOO anti-oxidative properties. These outcomes are exploitable towards the establishment of natural products like EVOO, as a preventive remedy fighting this neurodegenerative disorder, AD. Clinical trial registration MICOIL gov Identifier: NCT03362996
Observational epidemiological studies provide valuable information regarding naturally occurring protective factors observed in populations with very low prevalences of vascular disease. Between 1935 and 1965, the Italian-American inhabitants of Roseto (Pennsylvania, USA) observed a traditional Italian diet and maintained half the mortality rates from myocardial infarction compared with neighboring cities. In the Seven Countries Study, during 40years (1960-2000) Crete maintained the lowest overall mortality rates and coronary heart disease fatalities, which was attributed to strict adherence to the Mediterranean diet. In the French Three-City Study, a ten-year follow-up (2000-2010) showed that higher consumption of olive oil was associated with lower risk of death, as well as protection from cognitive decline and stroke. A large number of population-based studies and intervention trials have demonstrated that the Mediterranean diet is associated with lower prevalence of vascular disease, obesity, arthritis, cancer, and age-associated cognitive decline. Many of these effects are the result of consumption of fruits, seeds, legumes and vegetables but olive oil is the chief dietary fat in Mediterranean countries and the main source of monounsaturated fatty acids, as well as an important source of beneficial polyphenols and other antioxidants. Considering the critical role of vascular factors in the pathogenesis of late-onset Alzheimer disease it seems appropriate to focus on disease modification through proven dietary therapy. The authors base their hypothesis on meta-analyses of epidemiological data, numerous experimental studies, and a comprehensive review of the mechanisms of action of extra-virgin olive oil and its components in the prevention of vascular disease. In addition, extra-virgin olive oil has had positive effects on experimental animal models of Alzheimer disease. We therefore propose that extra-virgin olive oil is a promising tool for mitigating the effects of adverse vascular factors and may be utilized for potential prevention of late-onset Alzheimer disease.
Extra virgin olive oil (EVOO) polyphenols, including the secoiridoids oleocanthal (OLC) and oleacein (OLE), are attracting attention because of their beneficial effects on health. Data on OLC and OLE bioavailability are scarce, as most research on EVOO polyphenols has concentrated on hydroxytyrosol, tyrosol, and oleuropein. Consequently, relevant goals for future research are the elucidation of OLC and OLE bioavailability and finding evidence for their beneficial effects through pre-clinical and clinical studies. The aim of this review is to shed light on OLC and OLE, focusing on their precursors in the olive fruit and the impact of agronomic and processing factors on their presence in EVOO. Also discussed are their bioavailability and absorption, and finally, their bioactivity and health-promoting properties.