

Ci a ion: Jiménez-Sánchez, A.;
Ma ínez-O ega, A.J.; Remón-Ruiz, P.J.;
Piña -Gu ié ez, A.; Pe ei a-Cunill, J.L.;
Ga cía-Luna, P.P. The apeu ic
P ope ies and Use o Ex a Vi gin
Oli e Oil in Clinical Nu i ion: A
Na a i e Re iew and Li e a u e
Upda e. Nu ien s 2022,14, 1440.
h ps://doi.o g/10.3390/
nu14071440
Academic Edi o s: F anz Ma ín
and Ja ie S. Pe ona
Recei ed: 17 Feb ua y 2022
Accep ed: 25 Ma ch 2022
Published: 31 Ma ch 2022
Publishe ’s No e: MDPI s ays neu al
wi h ega d o ju isdic ional claims in
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ia ions.
Copy igh : © 2022 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
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condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
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4.0/).
nu ien s
Re iew
The apeu ic P ope ies and Use o Ex a Vi gin Oli e Oil in
Clinical Nu i ion: A Na a i e Re iew and Li e a u e Upda e
And és Jiménez-Sánchez 1,2,*, An onio Jesús Ma ínez-O ega 2,3 , Pablo Jesús Remón-Ruiz 1,2 ,
Ana Piña -Gu ié ez 1,2 , JoséLuis Pe ei a-Cunill 1,2 and Ped o Pablo Ga cía-Luna 1,2,*
1Unidad de Ges ión Clínica de Endoc inología y Nu ición, Hospi al Uni e si a io Vi gen del Rocío, A da.
Manuel Siu o s/n, 41013 Se ille, Spain; pabloj. [email p o ec ed] (P.J.R.-R.);
ana.pina [email p o ec ed] (A.P.-G.); josel.pe [email p o ec ed] (J.L.P.-C.)
2Ins i u o de Biomedicina de Se illa (IBiS), Hospi al Uni e si a io Vi gen del Rocío/CSIC/Uni e sidad de
Se illa, A da. Manuel Siu o s/n, 41013 Se ille, Spain; [email p o ec ed]
3Unidad de Ges ión Clínica de Endoc inología y Nu ición, Hospi al To ecá denas, C. He mandad de
Donan es de Sang e, s/n, 04009 Alme ía, Spain
*Co espondence: [email p o ec ed] (A.J.-S.);
[email p o ec ed] (P.P.G.-L.)
Abs ac :
Ex a i gin oli e oil (EVOO) is a co ne s one o he Medi e anean die (MedD). In his
na a i e e iew, we syn hesize and illus a e he a ious cha ac e is ics and clinical applica ions
o EVOO and i s componen s—such as oleic acid, hyd oxy y osol, and oleu opein—in he ield
o clinical nu i ion and die e ics. The e idence is spli in o die he apy, oleic acid-based en e al
nu i ion o mula ions and o al supplemen a ion o mula ions, oleic acid-based pa en e al nu i ion,
and nu aceu ical supplemen a ion o mino componen s o EVOO. EVOO has di e se bene icial
heal h p ope ies, and cu en e idence suppo s he use o whole EVOO in die he apy and he
supplemen a ion o i s mino componen s o imp o e ca dio ascula heal h, lipop o ein me abolism,
and diabe es melli us in clinical nu i ion. Ne e heless, mo e in e en ion s udies in humans a e
needed o chisel speci ic ecommenda ions o i s he apeu ic use h ough di e en o mula ions in
o he speci ic diseases and clinical popula ions.
Keywo ds:
oli e oil; Medi e anean die ; en e al nu i ion; pa en e al nu i ion; oleic acid;
hyd oxy y osol
;
oleu opein; oleocan hal; diabe es melli us; cance
1. In oduc ion
Oli e oil (OO) is he juice o he Olea eu opaea ui . When i is ob ained by physical
p ocesses and wi hou any u he ea men o he han washing, decan a ion, cen i u-
ga ion, and il a ion, i is conside ed i gin oli e oil. When VOO eaches he highes
s anda ds se by he EU Commission Regula ion No 2568/91 [
1
] and he T ade S anda d
o he In e na ional Oli e Council (IOC) [
2
], i can be classi ied as ex a i gin oli e oil
(EVOO). Bo h egula ions sha e he ollowing equi emen s in chemical composi ion o
de ine an OO as EVOO: a ee acidi y (exp essed as pe cen age o ee oleic acid)
≤
0.8
◦
%, a
pe oxide alue
≤
20 mEq O
2
/kg, UV spec ome y alues ha e lec minimal oxida ion
(K270
≤
0.22;
K232 ≤2.50
;
∆
K
≤
0.01), a a o able o ganolep ic assessmen (median o
0 de ec s and median o “ ui y” la o >0), and a pe cen age o a y acid e hyl es e s
(FAEEs)
≤
30 mg/kg o EVOO (in c ops ha es ed since 2015). The IOC also has a highe
FAEE h eshold (
≤
35 mg/kg o EVOO) and includes u he quali ying c i e ia, such as
≤
0.20% o mois u e and ola ile ma e in he oil,
≤
0.10% insoluble impu i ies in ligh
pe oleum, and low le els o ace me als (
≤
3.0 o i on and
≤
0.1 o coppe ). I an OO
complies wi h all he quali y c i e ia o be de ined as EVOO, hen pu i y c i e ia mus be
me o main ain his ce i ica ion, such as a
≤
0.05 s igmadiene con en (mg/kg o EVOO),
small amoun s o ans-isome s o unsa u a ed a y acids (
≤
0.05 o he sum o C18:1
Nu ien s 2022,14, 1440. h ps://doi.o g/10.3390/nu14071440 h ps://www.mdpi.com/jou nal/nu ien s
Nu ien s 2022,14, 1440 2 o 36
and
≤
0.05 o he sum o C18:2 and C18:3), a y acid con en unde speci ic h esholds
( o my is ic, linolenic, a achidic, eicosenoic, behenic, and lignoce ic acids),
∆
ECN42 ( he
di e ence be ween he heo e ical and measu ed ECN42 by HPLC)
≤
|0.2|, le els o 2-
glyce yl-monopalmi a e (depending on he palmi ic acid pe cen age), ce ain equi emen s
ega ding s e ols (a o al s e ol con en
≥
1000 mg/kg o EVOO, ixed maximum pe cen -
ages o choles e ol, b assicas e ol, campes e ol, s igmas e ol,
∆
-7-s igmas e ol, and he
appa en sum o
β
-si os e ol, as well as a sum o e y h odiol and u aol
≤
4.5%), and o al
waxes (
C42 + C44 + C46
)
≤150 mg/kg
o EVOO. The IOC has ex a c i e ia, such as ixed
anges o o he ee a y acids (palmi ic, palmi oleic, hep adecanoic, hep adecenoic, s ea ic,
and linoleic) and a highe h eshold o eicosenoic acid (
≤
0.50 ins ead o
≤
0.40) and o al
unsaponi iable ma e (≤15 g/kg o EVOO).
EVOO has been a co ne s one in he ci iliza ions ha ha e de eloped o e millennia
in he Medi e anean Basin. Since an iqui y, peoples o he Ma e Nos um ha e been awa e
o i s bene icial p ope ies o heal h and ha e used his p oduc in hei gas onomy and
pha macopoeia [
3
–
5
]. The aim o his na a i e e iew is o syn hesize and illus a e he
a ious cha ac e is ics, clinical applica ions, and mechanisms o ac ion o EVOO and i s
componen s in he ield o clinical nu i ion and die e ics. Mo e speci ically, he ollowing
mino opics a e discussed: die he apy, en e al nu i ion, o al nu i ional supplemen a ion,
pa en e al nu i ion, and nu aceu ical supplemen s. Ou ocus is on in e en ion s udies
in humans. When no a ailable, e idence om o he ype o s udies and/o animal models
is e iewed.
2. Ma e ials and Me hods
Each mino opic was indi idually explo ed in a comp ehensi e na a i e li e a u e
e iew du ing Oc obe –No embe 2021 using PubMed and Web o Science sea ch engines.
MeSH e ms we e used when applicable, and di e en sea ch s a egies we e unde aken
combining he ollowing keywo ds: “Medi e anean die ”, “ex a i gin oli e oil”,“oli e oil”,
“en e al nu i ion”,“pa en e al nu i ion”,“oleic acid”,“ y osol”,“hyd oxy y osol”, “phenolic”,
“oleu opein”,“oleocan hal”,“oli e lea ”,“oli e mill was ewa e ”,“an ioxidan ”,“in lamma *”,
“glucose”,“choles e ol”,“me abolic synd ome”,“diabe es”,“obesi y”,“lipop o ein”,“cance ”,
“ ascula ”,“hea ”,“os eopo osis”,“bone”,“p os a *”,“in es inal”,“neu o*”,“Alzheime ”,“ a y
li e ”,“elde *”,“mic obio*”, and “a h i is”. Ou p ima y sea ch was conduc ed in humans
and in e en ion s udies. I no e idence was a ailable, hen a seconda y sea ch was
conduc ed selec ing o he ype o s udies and/o animal models. Finally, in o ma ion was
pooled and syn hesized.
3. Resul s
3.1. Cha ac e is ics o EVOO
3.1.1. Chemical Composi ion
The chemical composi ion o EVOO depends, among o he s, on he place o p oduc-
ion, cul i a , and deg ee o ipeness o he oli es, which can a y signi ican ly [
6
–
11
]. F om
a chemical pe spec i e, EVOO can be di ided in o h ee main g oups o subs ances:
1.
Saponi iable ac ion. Accoun s o 98.5–99.5% in o al weigh [
6
–
9
,
12
–
14
]. I is mainly
made up o he ollowing:
(1)
F ee a y acids. The mos equen a e palmi ic (C16:0), palmi oleic (C16:1),
s ea ic (C18:0), oleic (C18:1), linoleic (C18:2), and linolenic (C18:3) acids. My is-
ic (C14:0), hep adecanoic, and eicosanoic acids a e also p esen in small
amoun s [
6
–
9
,
12
–
14
]. See Table S1 o u he in o ma ion on he pe cen ages
o a y acids p esen in EVOO om he main cul i a s in he Medi e anean
A ea [6,15–26].
(2)
T iglyce ides (TAGs) accoun o 99% o he saponi iable ac ion. The mos
p e alen (43.5%) is iolein, composed o h ee chains o acid. O he es e i ica-
ion possibili ies a e one palmi ic acid in posi ion sn-3 and wo oleic acids in
Nu ien s 2022,14, 1440 3 o 36
sn-1 and sn-2 posi ions (accoun ing o 18.4% o TAGs), as well as one linoleic
acid in sn-2 posi ion bo de ed by wo oleic acids (6.8%) [6–9,12–14].
(3)
Pa ial acylglyce ols (diacylglyce ols, DAGs, o monoacylglyce ols, MAGs).
Thei p esence in EVOO is due o incomple e iacylglyce ol biosyn hesis o
hyd oly ic eac ions. A good-quali y oil should ha e no mo e han 1–2.8%
DAGs, wi h highe alues being conside ed an indica ion o poo p ocess-
ing o s o age. The 1,2-DAGs— ypical o eshly p oduced oil—g adually
ans o m in o he mo e s able 1,3-DAGs. The e o e, he 1,3-DAG/1,2-DAG
a io is conside ed a eliable pa ame e o de e mine he age o EVOO. MAGs
a e much less p e alen (less han 0.25%) and a y widely acco ding o he
p oduc ion a ea: Spanish, Po uguese, I alian, o G eek OOs a e iche in oleic-
based MAGs, while Tunisian OOs a e iche in palmi ic- and linoleic-based
MAGs [6–9,12–14].
2.
Unsaponi iable ac ion. Cons i u es 0.5–1.5% o EVOO. I can be g ouped in o
he ollowing:
(1)
Tocophe ols. The mos abundan is
α
- ocophe ol (150 o 250 mg / kg o EVOO).
The op imal a io o i amin E o polyunsa u a ed a y acids o 1.5–2.0.
α
-
Tocophe ol is able o neu alize ee adicals and p e en pe oxida ion o
memb ane lipids and low-densi y lipop o eins (LDLs).
β
- ocophe ol (15–20%)
and γ- ocophe ol (7–23%) a e p esen in smalle p opo ions [6–9,12–14].
(2)
Phy os e ols. The amoun a ies om 100 o 250 mg/100 g o EVOO. S e ols a e
ca ego ized in o 4,4-dime hyls e ols o i e penic alcohols ( wo me hyl g oups
a he C-4 posi ion), 4-monome hyls e ols o me hyls e ols (one me hyl g oup
a he C-4 posi ion), and 4-desme hyls e ols o phy os e ols (no me hyl g oup),
he la e being he main s e ols in EVOO [
6
]. EVOO has many phy os e ols,
such as
β
-si os e ol, campes e ol,
∆
5-a enas e ol, s igmas e ol, choles e ol,
choles e ol, b assicas e ol, si os anol, e gos e ol, campes anol,
∆
7-choles enol,
∆
7-a enas e ol,
∆
7-s igmas e ol,
∆
7-campes e ol,
∆
5,24-s igmas adienol,
∆
5,23-
s igmas adienol,
∆
7,24-e gos adienol,
∆
7,22-e gos adienol, 22,23-dihyd o
b assicas e ol, and 24-me hylene-choles e ol [
27
]. The main one is
β
-si os e ol,
accoun ing o 75–90% o o al phy os e ols in EVOO [
28
]. Di e en ege able
oils ha e di e en p opo ions o phy os e ols, such as highe campes e ol o
seed oil, and
∆
7-s igmas enol o sun lowe and sa on oil [
29
]. The IOC and
EU Commission de ine he s e ol “ inge p in ” o EVOO as ha wi h >93.0%
o appa en
β
-si os e ol, which is he sum o he pe cen ages o
β
-si os e ol
plus
∆
5,23-s igmas adienol, si os anol,
∆
5-a enas e ol,
∆
5,24-s igmas adienol,
and chle os e ol [
1
,
2
]. Fo example, EVOOs om Picholine and Sinopolese
cul i a s in I aly ha e shown high and s eady amoun s o
β
-si os e ol h ough
di e en seasons [
30
]. On he o he hand, hese egula ions also limi he ela-
i e p opo ion o e y h odiol and u aol as 4.5% [
1
,
2
], as excessi e amoun s o
hese i e penes may be a sign o adul e a ion wi h oli e pomace oil o g ape
seed oil. Fo example, EVOOs om Manzanilla Cace eña in Spain a e well
unde his limi [31].
3. O he mino componen s a e he ollowing:
(1)
Phenolic compounds. They a e di ided in o phenolic acids (p-couma ic, gallic,
anillic, and ca eic acid, as well as o he s), la onoids (lu eolin, apigenin, and
hei de i a i es), lignans (pino esinol and 1-ace oxypino esinol), isoch omans
(1-phenyl-6,7-dihyd oxy-isoch oman, and 1-(30-me hoxy-40-hyd oxy)phenyl-
6,7-dihyd oxy-isoch oman), secoi idoids (deme hyloleu opein, oleu opein,
ligs oside, and hei aglycone de i a i es), and phenolic alcohols ( y osol, hy-
d oxy y osol, and homo anillyl alcohol) [
27
]. Ty osol, 5-hyd oxy y osol, and
i s elenoic acid es e —oleu opein—ha e po en an ioxidan ac i i y
in i o
and
in i o
, along wi h an i-in lamma o y ac i i y. Combining an
in i o
Nu ien s 2022,14, 1440 4 o 36
and
in i o
app oach, i was demons a ed ha oleocan hal (a secoi idoid
de i a i e) is a po en ac i a o o he ansien ecep o po en ial anky in 1
(TRPA1) ion channel exp essed in igeminal senso y neu ons. When ac i a ed,
TRPA1 c ea es a Ca
2+
-media ed cell depola iza ion in e p e ed as a pungen
sensa ion ha igge s a de ensi e cough esponse, o p e en he en ance o
po en ially ha m ul compounds o he ai way. This e ec akes place mainly
in he pha ynx—whe e he densi y o TRPA1 ecep o s doubles ha o he
ongue—and independen ly o he lipophilici y o he ood ma ix [
32
]. Smalle
amoun s o simple phenolic compounds—such as ca eic, anillic, and e -
ulic acids—ha e he ole o p o ec ing and enhancing he bioa ailabili y o
α
- ocophe ol [
6
–
9
,
12
–
14
,
33
,
34
]. See Table S2 o u he in o ma ion ega ding
an ioxidan s in he unsaponi iable ac ion o EVOO om he main cul i a s in
he Medi e anean A ea [17,19–23,25,35–51].
(2) Chlo ophyllic and ca o enoid pigmen s. P esen in small amoun s, hey colo
EVOO. O no e a e β-ca o ene and lycopene. [6–9,12–14].
(3)
Vola ile compounds. Mo e han 100 ola ile compounds a e esponsible o he
cha ac e is ic odo o EVOO. These a e small molecules (<300 Da) ha apo ize
a oom empe a u e [
52
] and a e p esen in EVOO’s headspace in highe
concen a ions han lowe -quali y OOs [
53
,
54
]. The majo ola ile compounds
in EVOO a e C6 and C5 alcohols and aldehydes o med om polyunsa u a ed
a y acids (PUFAs) h ough he lipoxygenase pa hway. Al hough he o me
a e p esen in highe quan i ies, he la e ha e lowe de ec ion h esholds
in ol ac o y ecep o s [
55
]. 2(E)-Hexenal is he main C6 aldehyde in EVOO,
gi ing “g een” and “ ui y” no es o EVOO, while C5 aldehydes and alcohols
gi e pungen sensa ions [
56
] ha may be app ecia ed by consume s [
57
]. The
concen a ion o ola ile compounds in EVOO depends on he cul i a and
geog aphical a ea whe e he oli e ee li es [
58
]; hence, EVOOs wi h di e en
o igins can be so ed by hei cha ac e is ic p o iles [
59
]. Using his app oach,
a s udy clus e ed 18 I alian cul i a s in o eigh g oups on he basis o hei
dis inc le els o e hanol, 2-me hyl p opanol, pen anol, cis-2-pen en-1-ol, cis-
3-hexenol, and oc anol [
60
]. Un ipe ui is associa ed wi h hexanal, ans-
3-hexexnol, cis-3-hexen-1-ol, and cis-2-hexenol, associa ed wi h compelling
senso y a ibu es such as “ ui y”, “g assy”, and “pungen ” [
61
]. Highe
oxygena ion [
62
] and empe a u es a ound 20
◦
C du ing malaxa ion [
63
], as
well as an adequa e s o age empe a u e [
64
] and minimiza ion o s o age
ime [62], maximize he amoun and quali y o EVOO’s ola iles.
(4)
Alipha ic alcohols o a y alcohols (FAL). They a e use ul o classi y di e en
ca ego ies o OO in ela ion o he wax con en o he p oduc . E en-chain FALs
(ECFALS) a e mo e equen han odd-chain FALs (OCFALs). Policosanol is
he mix u e o he mos common ECFALs: docosanol (C22), e acosanol (C24),
hexacosanol (C26), and oc acosanol (C28). Policosanol con en in EVOO is
egula ed by he IOC and EU Commission [
1
,
2
]. Acco ding o p e ious s udies,
hexacosanol seems o be he mos abundan FAL in C oa ian [
65
], G eek [
66
],
I alian [
67
], Spanish [
68
], and Tunisian [
69
] cul i a s. The FAL con en o EVOO
depends mainly on he cul i a [
67
]. Bo h OCFAL and ECFAL quan i ies de-
c ease wi h he inc eased ipening o he ui , bu he e a e di e ences be ween
s udies ega ding he FAL mos a ec ed by ipening. I was hexacosanol in
I alian cul i a s [70] and pen acosanol in C oa ian cul i a s [65].
(5)
Alkanes and alkenes. These linea hyd oca bons occu na u ally in EVOO
as p ecu so s du ing wax biosyn hesis. Alkanes and alkenes a e mos ly odd-
numbe ed, as hey come om he loss o a ca boxyl g oup in e y-long-chain
acids (VLCA), which a e ini ially o med by he a y-acid elonga ion com-
plex in he endoplasmic e iculum (using palmi ic and s ea ic acids as sub-
s a es) [
71
]. The alkane con en and p o ile in EVOO depend on i s cul i-
Nu ien s 2022,14, 1440 5 o 36
a [
72
], ha es ime [
73
], and geog aphical egion: he mos equen n-
alkanes a e n-C25 in con inen al Eu ope, n-C23 in no h A ica and sou he n
I aly, and n-C29 in he Ibe ian Peninsula [
73
,
74
]. This di e en geog aphical
loca ion may be ela ed o me eo ological condi ions, as he in ensi y o p ecip-
i a ion is associa ed wi h la ge alkanes and alkenes [
75
]. In addi ion o hei
use ulness in acing he geog aphical o igin and cul i a o EVOO, alkanes
and alkenes a e also use ul o de ec ing coun e ei s, because ege able oils, as
well as oli e oils o di e en quali ies, ha e dis inc i e inge p in s ega ding
hese compounds. Alkanes a e abso bed and hen me abolized o FALs in he
small in es ine [72].
3.1.2. P oduc ion o EVOO and I s Mino Componen s
The p o ile and concen a ion o compounds in he unsaponi iable ac ion o EVOO
depend on he cul i a [
76
], i iga ion [
77
], mode o cul i a ion [
47
], and ipening o he
ui [
78
]. Cul i a , ime, and g owing condi ions can modi y he exp ession o he
β
-
glucosidase, a main enzyme in he syn hesis o secoi idoid de i a i es in Olea eu opaea [
79
].
Malaxa ion empe a u e [46] and s o age empe a u e [80,81] may also a ec he phenolic
con en o EVOO. Du ing s o age, he e is ime-dependen con e sion o hei secoi idoids
and de i a i es (mainly oleacein and oleocan hal) in o byp oduc s such as hyd oxy y osol
and oleocan halic acid. Du ing his p ocess, di e en cul i a s and geog aphical a eas
may p esen di e en ans o ma ion pa e ns [
82
]. The e is no ac ual consensus on he
de ini ion o EVOO wi h high phenolic con en . Some au ho s ha e p oposed EVOOs wi h
>500 mg o polyphenols pe kg o p oduc [
76
]. Polyphenols and o he mino componen s
can be ex ac ed om oli e pomace, oli e mill was ewa e , and oli e lea es, c ea ing a
ci cula ag icul u e sys em. The phenolic p o ile o hese non-oil sou ces o polyphenols is
dis inc i e. Amongs hem, oli e ee lea es ha e he highes yield o phenols due o hei
g ea e con en o secoi idoids (mainly oleu opein) [
83
,
84
]. The majo de e minan o he
phenolic yield o oli e ee lea es is he ype o cul i a [
85
]. O he ac o s a e he colo [
86
]
and d yness o he lea es [
87
], as well as he geog aphical loca ion o he oli e ee and lea
collec ion ime [88].
3.1.3. Cooking wi h EVOO
C ude EVOO is he ideal ood ma ix o abso p ion o i s hyd oxy y osol in he in-
es ines, ensu ing maximum concen a ions in blood [
89
,
90
]. Among hea -based cooking
me hods, ying and s eaming may p ese e o enhance EVOO’s an ioxidan capaci y, while
sau éing, p essu e cooking, boiling, and mic owa ing may lead o signi ican educ ions in
i s o al phenolic con en [
91
,
92
]. When boiling ege ables in a p essu e cooke , phenolic
compounds a e ans e ed o cooking wa e om bo h EVOO and ege ables, wi h a maxi-
mum ans e in he case o eggplan , oma o, and pumpkin [
92
]. The e o e, inco po a ing
his cooking wa e in o he inal ecipe—ins ead o disca ding i —may be o in e es o he
consume . Du ing boiling, secoi idoids a e ans o med in o y osol, which is inc eased,
while ocophe ol con en is lowe ed. In e es ingly, hyd oxy y osol con en may inc ease o
he i s hou s when using EVOO o he Picual cul i a , while he in ensi y o loss o o al
phenolic con en may be cul i a -dependen [93].
Du ing ying, hyd oxy y osol and y osol may ha e he lowes he mal esis ance,
and deep ying and pan ying may a ec he ype o phenolic compounds los du ing
hea ing [
94
]. When ying wi h EVOO, empe a u e seems a much mo e impo an ac o
han ime; app oxima ely, i s phenolic con en can be dec eased by 40% a 120
◦
C and 75%
a 170
◦
C wi h 15–60 min o cooking [
95
], while i s sca enging ac i i y may be hal ed
a app oxima ely 180
◦
C a e jus 15 min [
96
]. Du ing in ensi e hea ing (180–220
◦
C
o 30–120 min), EVOO can deg ade mo e han o he ege able oils such as pomace,
soybean, and palm oil, de eloping highe le els o pe oxides and ee a y acids, as well
as unde going he highes ela i e loss in phenolic con en [
97
]. Ne e heless, EVOO is
mo e esis an o oxida ion [
98
] and may p oduce highe yields o ocophe ols a 180
◦
C

Nu ien s 2022,14, 1440 6 o 36
han o he monounsa u a ed a y acid (MUFA)- ich cooking oils [
99
]. In his ega d, using
OO o y blue ish (ano he impo an componen o heMedD) may ans e signi ican
amoun s o squalene o he ood ma ix and p o ec i s
ω
-3 con en be e han sun lowe
oil [
100
]. In his p ocess, he loss o hyd oxy y osol and i s secoi idoids seems o be g ea e
han he loss o y osol and i s de i a i es [
101
]. In e es ingly, he loss o o al phenolic
con en unde ying seems o ake place ea ly du ing cooking and s abilize om 60 min o
cooking [
102
]. Unde hese condi ions, 2(E)-hexenal con en is d as ically educed in a ime-
and empe a u e-dependen manne , while new and undesi able ola iles appea due o
oleic acid oxida ion, hus educing i s senso y p ope ies [103].
In a head- o-head s udy, mic owa ing o 5 min a 500 W did no gene a e signi ican
losses in o al phenolic con en , while baking a 180
◦
C o 45 was associa ed wi h an
11% loss. In any case, bo h me hods we e less de imen al o he phenolic con en han
boiling a 100
◦
C o 40–80 min o ying a 180
◦
C o 1–5 h [
1
]. Ne e heless, mic owa -
ing EVOO a 500 W o longe pe iods o ime is no ecommended, as i may gene a e
quan i a i ely g ea e oxida ion and loss o phenolic con en [
104
], as well as as e la o
de e io a ion h ough he o ma ion o ac olein. Ne e heless, hese esul s a e limi ed
by ce ain expe imen al condi ions (mic owa e and o en samples did no ha e he same
olume) [
105
]. Al hough lipid oxida ion akes place du ing baking, he subs i u ion o
ma ga ine o EVOO in bake y p oduc s can p e en iglyce ide oxida ion and inc ease
i s shel li e [
106
] wi hou subs an ially al e ing he senso y and physical p ope ies o he
ood [
107
]. This may be due o a g ea e p esence o an ioxidan molecules in he inal
p oduc . In his ega d, oleu opein le els may be highe in s a ch ma ices ha ha e been
baked ins ead o boiled, while ha ing g ea e bio-accessibili y han lipid-based ca ie s [
90
].
A s udy on Caco cells sugges ed he e may no be a close co ela ion be ween he o al
phenolic con en o a ce ain polyphenol-en iched bake y p oduc and i s abili y o exe
an i-in lamma o y p ope ies, as i depends on he di e en bio-accessibili y and bioa ail-
abili y o each o hese compounds. This may depend on he sou ce o phenolic compounds,
he ype o molecule, he cha ac e is ics o he e men a ion p ocess, and he selec ed ime
and empe a u e du ing baking [108].
Consuming EVOO wi h egg o whey p o ein [
109
] and o i ying oods wi h polyphe-
nols o secoi idoids may be o in e es o people wi h an a e sion o he bi e as e o
hese compounds [
110
]. Liquid p epa a ions wi h oleu opein in compa ison wi h capsules
ha e shown a highe plasma peak o oleu opein and a as e abso p ion o hyd oxy y osol
me aboli es [
111
], which could explain he g ea e he apeu ic e icacy associa ed wi h his
pha maceu ical p epa a ion [
112
]. Polyphenol abso p ion occu s in p oximal sec ions o
he small in es ine in humans [
113
]. D ugs can in e e e wi h he abso p ion o
β
-si os e ol.
Eze imibe is an app o ed ea men o phy os e olemia [
114
] ha inhibi s
β
-si os e ol
abso p ion ei he as mono he apy [
115
] o in combina ion wi h s a ins [
116
].
β
-Si os e ol
abso p ion inc eases wi h a o as a in [117].
3.1.4. Abso p ion and Me aboliza ion o EVOO and I s Mino Componen s
Secoi idoid de i a i es and phenolic acids a e hyd oxyla ed in he mou h, s omach,
and duodenum, eleasing phenolic alcohols ( y osol and hyd oxy y osol) [
45
] This ans-
o ma ion can be enhanced
in i o
in mice wi h he addi ion o he p obio ic Lac obacillus
plan a um [
118
]. In e es ingly, he bio-accessibili y ( ac ion o bioac i e compounds eed
om he ood ma ix and a ailable o hei in es inal abso p ion) o phenolic compounds
may be no only dose-dependen , bu also con ingen upon he di e en s abili y o hese
compounds wi h ega d o diges i e ac condi ions and he cha ac e is ics o he ood
ma ix. In a s udy wi h
in i o
enzyma ic diges ion o EVOOs om i e di e en cul i-
a s, Se illana had he lowes o al phenolic con en (571
±
1.6 nmol/g o EVOO) and
he second lowes hyd oxy y osol con en (6.11
±
0.0 nmol / g o EVOO), ye he highes
bio-accessibili y index o o al phenolic compounds (36%) and hyd oxy y osol (2452%) [
45
].
Rega ding he abso p ion o oli e lea ex ac s, a s udy ound a o al phenolic con en o 94
±
2 mg/g o d y ex ac , wi h oleu opein as i s majo cons i uen (76.1
±
0.8 mg/g o d y
Nu ien s 2022,14, 1440 7 o 36
ex ac ). In his case, oleu opein also p esen ed he highes bio-accessibili y index (109.86%)
a e 240 min o enzyma ic diges ion [
119
]. Fu he s udies ocusing on he bio-accessibili y
o polyphenols a e enzyma ic diges ion o di e en Olea eu opaea p oduc s ha e been
ex ensi ely e iewed elsewhe e [
120
]. Oleu opein and hyd oxy y osol an ioxidan ac i i y
seemed o be simila in an ex i o s udy in humans [
121
], while bo h seemed o be mo e
po en han homo anillic alcohol
in i o
[
122
]. Hyd oxy y osol plasma concen a ions
diminish wi hin app oxima ely 1 h a e EVOO inges ion, as hey a e ans o med in o
glucu onida ed o ms, which ha e simila an ioxidan po ency o y osol [
123
]. In humans,
he abso bed die a y y osol is me abolized o hyd oxy y osol and homo anillic alcohol in
he li e by he CYP2A6 and CYP2D6 enzymes [124].
Al hough phy os e ol and phy os anol abso p ion in humans is poo ,
∆
5-phy os e ols
(si os e ol and campes e ol) may ha e highe abso p ion and lowe u no e a es han
5
α
-phy os anols (si os anol and campes anol) [
125
]. This abso p ion akes place using
he Niemann-Pick 1C-like 1 anspo e (NPC1L1), he same ou e used by choles e ol.
The e o e, he inhibi ion o choles e ol abso p ion is compe i i e and dose-dependen .
A e wa d, phy os e ols a e hen es e i ied wi hin en e ocy es and inco po a ed in chylomi-
c ons o each he li e . Finally, hepa ocy es sec e e hese phy os e ols in o he bile h ough
ABCG5/G8 anspo e s [
126
]. Phy os e ol composi ion, he cha ac e is ics o i s ood ma-
ix, clinical condi ions ha a ec choles e ol me abolism such as ype 2 diabe es melli us
(DM2), and single-nucleo ide polymo phisms (SNPs) in NPC1L1 and apolipop o ein E
(ApoE) may modi y bo h hei bioa ailabili y and hei e icacy [126,127].
3.1.5. Rele an E ec s o EVOO on Pa hophysiological P ocesses
Al hough EVOO has a high concen a ion o MUFA (oleic acid) compa ed o o he
a y acids, EVOO’s mino componen s appea o be esponsible o he g ea es numbe o
i s bene icial e ec s. The e is abundan e idence abou he mechanisms o ac ion and he
he apeu ic po en ial o capaci y o hese mino componen s, mainly in animal models o
ex i o s udies in humans. The ollowing is a e y b ie summa y o he mos clinically
ele an e idence on he e ec s o EVOO:
1.
An i-in lamma o y. Consump ion o EVOO in humans has shown signi ican educ-
ions in in lamma o y and cell adhesion media o s such as, bu no limi ed o, ascula
cell adhesion molecule 1 (VCAM-1), in e cellula adhesion molecule 1 (ICAM-1),
in e leukin 6 (IL-6), and C- eac i e p o ein (CRP), bo h p e-p andially and pos p an-
dially. A e consuming a meal ich in EVOO, educed le els o h omboxane B2,
leuko iene B 4, umo nec osis ac o -
α
(TNF-
α
) mRNA, a achidonic acid syn hesis,
and na u al kille (NK) cell ac i i y ha e been obse ed in ex i o human s udies.
These e ec s could be media ed—among o he mechanisms—by di ec ac i a ion
o pe oxisome p oli e a o -ac i a ed ecep o s-
α
/
γ
(PPAR-
α
/
γ
), ep ession o nu-
clea ac o kappa-ligh -chain-enhance o ac i a ed B cells (NF-
κ
B), inhibi ion o
cyclooxygenases 1 and 2 (COX1-COX2), lipoxygenases, MAP kinases (MAPK), and
Janus kinases / signal ansduce and ac i a o o ansc ip ion p o eins (JAK/STAT)
pa hways [12,14,128–130].
2.
Coagula ion. EVOO appea s o inhibi pla ele adhesion by dec easing he on Wille-
b and ac o exp ession, and egula consump ion o EVOO may also educe ac o VII
ac i a ion and ci cula ing plasminogen ac i a o inhibi o -1 (PAI-1) le els. [
12
,
13
,
128
].
3.
Vasodila ion. In mu ine models, i e penes gene a e ao ic asodila ion in a NO-
dependen and COX-independen manne [
131
] ha is endo helium-media ed [
132
].
EVOO’s mino componen s may also nega i ely egula e ACE and NR1H2 genes [
130
].
4.
Imp o ed endo helial heal h and lipop o ein composi ion. The combina ion o he
p e iously desc ibed p ope ies o EVOO allows i o imp o e endo helial unc-
ion
[12,14]
and educe he isk o a he oma ous plaque de elopmen o compli-
ca ion [
12
–
14
,
128
,
130
]. Regula consump ion o EVOO inc eases he high-densi y
lipop o ein (HDL) ac ion and he phenolic con en o LDLs, imp o ing hei esis-
Nu ien s 2022,14, 1440 8 o 36
ance o oxida ion and, hus, educing hei a he ogenic capaci y. Al hough mixed,
some e idence indica es ha EVOO may also educe abdominal adiposi y [130].
5.
Con ol o cell p oli e a ion. Phenolic compounds, such as oleocan hal, a e able o ac
on he exp ession o genes ha con ol he p oli e a ion, apop osis, and di e en ia ion
o cance cells [
13
,
33
,
34
,
133
]. The e is
in i o
e idence showing ha polyphenols in
EVOO al e mic oRNAs in cance cells, while hyd oxy y osol appea s o exe s ong
an ip oli e a i e e ec s in human colon adenoca cinoma cells [14].
6.
Mic obiological p ope ies. Oleu opein has
in i o
an imic obial ac i i y agains
mul iple G am-posi i e and G am-nega i e bac e ia, mycoplasma, and i uses [
134
].
Some o hese mic oo ganisms a e o pa icula in e es , such as me hicillin- esis an
S aphylococcus au eus (MRSA) [
135
]. Oleu opein caused imp o ed su i al in an an-
imal model o mul id ug- esis an Pseudomonas ae uginosa sepsis, explained by ex
i o s imula ion o phagocy osis and inhibi ion o p oin lamma o y cy okines [
136
].
Hyd oxy y osol has shown ex i o and
in i o
an i-HIV-1 ac i i y in abbi s, wi h no
associa ed oxici y [
137
]. EVOO consump ion has been linked o inc eased p opo -
ions o Clos idium clus e XIVa and Bi idobac e ium,Pa asca do ia, Bac e oides agilis,
and Lac obacillus johnsonii, as well as a educ ion o he p esence o Lac obacillus an-
imalis, Lac obacillus aiwanensis, Lac ococcus spp., P o eobac e ia, De e ibac e es, and
Rikenella [130].
7.
Bone homeos asis. In an animal model, bo h hyd oxy y osol and y osol appea ed o
ha e a posi i e e ec on bone heal h [
128
].
In i o
s udies in he human os eoblas
cell line MG63 ha e shown di e en ial e ec s o ca eic, e ulic and couma ic acid,
apigenin and lu eolin on gene exp ession [
138
,
139
]. The addi ion o di e en a ie ies
o EVOO—wi h unique composi ions in mino componen s—had di e gen e ec s on
he di e en ia ion, an igenic exp ession, and an igenic capaci y o his cell line [140].
8.
Ca diac unc ion. In animal models, oleu opein p o ec ed in a dose-dependen ashion
agains loss o ejec ion ac ion and ca diac ou pu due o myoca dial in a c ion a
24 h
[
141
] and 5 weeks [
142
]. Oleu opein also p o ec ed in a edox-dependen manne
agains epe usion inju y in simila s udies [
143
,
144
]. In animal models, oleu opein
p e en ed myoca dial emodeling in hea ailu e—by inhibi ing he angio ensin-
con e ing enzyme [
145
], in doxo ubicin ca diomyopa hy—by modula ing ni ic
oxide syn hases and o he mechanisms [
146
], and in au oimmune myoca di is [
147
]
and sepsis-induced myoca dial inju y—by NF-
κ
B inhibi ion [
148
]. Oleu opein and
hyd oxy y osol exe an iapop o ic e ec s on ca diomyocy es by educing endoplas-
mic e iculum s ess [
149
]. In an animal model o obesi y, oleu opein and ca eic acid
imp o ed myoca diocy e ene gy yield wi hou imp o ing edox ma ke s [150].
9.
Amyloid p oduc ion. Oleu opein o e ed p o ec ion agains amyloid deposi ion in a
human cell line ha mimics amilial sys emic amyloidosis [151].
3.2. Use o EVOO in Die The apy
The Medi e anean die (MedD) is a die a y pa e n ypical o coun ies cha ac e ized
by hei abundance o oli e ees and he ex ensi e use o OO in hei die s, being hei main
sou ce o a . In e es in he MedD began in he 1960s wi h he Se en Coun ies popula ion-
based s udy, which obse ed up o h ee imes lowe mo ali y due o hea disease in
Medi e anean coun ies compa ed o hose o no he n Eu ope and he Uni ed S a es [
152
].
The composi ion o EVOO and i s e ec s on mul iple pa hophysiological p ocesses may
syne gize wi h o he ac o s in his die a y pa e n—which seem o be key o inducing
he bene icial e ec s o MedD—such as an ac i e li es yle wi h egula physical exe cise,
high ibe in ake, consump ion o oods na u ally ich in
ω
-3 a y acids, and compliance
wi h nu i ional ecommenda ions on mic o and mac onu ien composi ion, among o he s.
The consump ion o EVOO has shown bene icial e ec s in many di e en pa hologies, all
o which a e ela ed o i s an ioxidan , immunomodula o y, and in lamma o y esponse-
egula ing e ec s. Below, we summa ize he e idence o high-impac pa hologies in he
gene al popula ion.
Nu ien s 2022,14, 1440 9 o 36
1.
Ca dio ascula unc ion and heal h. The MUFA composi ion o EVOO has been
associa ed wi h be e pe iphe al insulin sensi i i y and glucose ole ance, educed
exogenous insulin equi emen s, imp o ed endo helial unc ion, and an i h ombo ic
p ope ies [
153
]. Clinical ials ha e shown ha he phenolic con en o EVOO is e-
sponsible o i s an ihype ensi e p ope ies [
154
,
155
] and i s imp o emen o as ing
and pos p andial lipid p o ile [
153
] in a dose-dependen manne [
156
] in di e en
clinical popula ions, including DM2 [
157
]. Clinical ials wi h polyphenol- ich EVOO
ha e also shown i s abili y o modi y le els o an ioxidan s, p oin lamma o y p o-
eins, bioma ke s o endo helial dys unc ion, and DNA and lipid oxida ion in a
dose-dependen manne , in a ious clinical popula ions [
155
,
158
–
163
]. In his ega d,
a me a-analysis o clinical ials—wi h a majo i y o heal hy adul s—con i med ha
high phenolic EVOO (de ined as
≥
200 mg/kg o phenolic con en ) has he g ea -
es impac in he educ ion o oxidized LDL-choles e ol (HR:
−
0.68; 95% CI:
−
1.31,
−
0.04) [
164
]. The PREDIMED s udy has been a miles one in his opic. I was an
unblinded clinical ial, designed o es he e icacy o MedD in he p ima y p e-
en ion o ca dio ascula majo e en s (a composi e o myoca dial in a c ion, s oke,
and dea h om ca dio ascula causes) in a high- isk ambula o y popula ion. The
ea men a m exposed o die a y aining o inc ease adhesion o MedD, and ou
ablespoons (app oxima ely 52 g) o EVOO pe day had a 31% isk educ ion (HR: 0.69;
95% CI: 0.53, 0.91) o ca dio ascula majo e en s [
165
]. An obse a ional pos - ial
ollow-up in he PREDIMED s udy ound a 10% isk educ ion (HR: 0.93; 95% CI: 085,
0.95) in ca dio ascula majo e en s o each 10 g o EVOO ha pa icipan s consumed
a baseline, independen o hei compliance o he MedD and o he con ounding
ac o s a ha momen [
166
]. A me a-analysis o coho s udies a ibu ed a educ ion
in ca dio ascula mo ali y o 21% o MedD [
167
]. Pa icipan s in he NHANES and
UPFS coho s ha consumed mo e han 7 g o OO pe day had a 19% isk educ ion
(HR: 0.81; 95% CI: 0.75, 0.87) in compa ison wi h hose ha ne e o seldom did [
168
].
The subs i u ion o an equi alen dose o ma ga ine o bu e o a ablespoon o OO
showed a 6% isk educ ion (HR: 0.94; 95% CI: 0.90, 0.97) in he NIH-AARP Die and
Heal h S udy coho [
169
]. Popula ion s udies also associa e EVOO consump ion
wi h educed ascula s i ness [
170
] and a ibu e he educ ion in ca dio ascula
mo ali y om MedD o hyd oxy y osol and i s me aboli es [
171
]. A clinical ial in
heal hy olun ee s ound ha EVOO imp o ed p o eomic ma ke s associa ed wi h
co ona y a e y disease, while no di e ences we e ound o hose associa ed wi h
ch onic kidney disease o diabe es [172].
2.
Lipop o ein me abolism. In 2011, he Eu opean Food Sa e y Au ho i y (EFSA) issued a
Scien i ic Opinion accep ing he bene i s o he daily in ake o 5 mg o hyd oxy y osol
and i s de i a i es om EVOO o p e en oxida ion o LDL pa icles in he gene al
popula ion [
173
]. In andomized, blinded, and c osso e clinical ials, he addi ion
o polyphenol- ich EVOO was shown o educe he exp ession o genes ela ed o
in lamma ion, a he ogenesis, oxida ion, me abolic synd ome, dyslipidemia, and DM2
in di e en clinical popula ions [
158
,
174
–
176
], as well as inc easing he exp ession o
genes in ol ed in choles e ol e lux o HDL pa icles in people wi h hype ension [
177
].
Simila ly, polyphenol- ich EVOO has he highes capaci y o imp o e he numbe ,
p opo ions, and mo phology o lipop o eins [
178
,
179
], due o he inco po a ion o
inges ed polyphenols in o hese pa icles [
180
]. Resul s om an animal model sugges
ha polyphenol supplemen a ion and exe cise may syne gize o achie e a g ea e
educ ion o oxidized LDL pa icles [
181
]. On he o he hand, an isocalo ic high-MUFA
(sou ced om sun lowe oil and ma ga ine), high- ibe , and choles e ol- es ic ed die
was able o main ain apolipop o ein AI le els while p o iding he same dec ease in
apolipop o ein B100 as an isocalo ic low-MUFA, high- ibe , and choles e ol- es ic ed
die in a clinical ial wi h people wi h dyslipidemia [182].
3.
Al e a ions in ca bohyd a e me abolism. MedD has been associa ed wi h weigh loss
and p o ec ion agains me abolic synd ome in humans [
156
]. The consump ion o
Nu ien s 2022,14, 1440 16 o 36
use o OO-based ILEs, hey should no be used in pa ien s wi h hype sensi i i y o egg, OO,
soy, peanu s, o any componen he eo . In addi ion, OO-based ILEs o mula ions should
be adminis e ed wi h cau ion in pa ien s equi ing an icoagulan he apy, as hei lipids
con ain only 10–50 µg/L o i amin K [250].
3.5. Supplemen a ion o Nu aceu icals om EVOO
In his sec ion, we summa ize he s udies ha supplemen ed mino componen s o
EVOO, ei he in isola ion o wi hin ood ma ices such as EVOO i sel . Mos o he a ailable
s udies we e conduc ed in he ollowing clinical popula ions:
1.
Diabe es. Human clinical ials ha e demons a ed ha oleu opein can imp o e
pos p andial glycemic esponse in heal hy indi iduals [
112
], in o e weigh people
wi hou impai ed ca bohyd a e me abolism [
265
], and in hose wi h ca bohyd a e
in ole ance [
266
] and DM2 a he expense o inc eased GLP1 and insulin, by educing
oxida i e s ess h ough inhibi ion o NADPH oxidase 2 (Nox2) [
267
]. In a andom-
ized, blinded clinical ial, oli e lea ex ac was also shown o imp o e pos p andial
glycemic esponse and me abolic con ol in people wi h DM2 [
268
]. In a p ospec-
i e s udy in people wi h hyd oca bon in ole ance, plasma
β
-si os e ol le el ac ed
as a p o ec i e ac o agains he de elopmen o DM2 [
269
]. Ex i o s udies in
humans ha e indica ed ha oleu opein and hyd oxy y osol can inhibi
α
-amylase,
α
-glucosidase, suc ase, lipase, and glucose anspo e 2 (GLUT-2) [
112
,
270
–
272
]. In
animal models, oleanolic acid and lu eolin ha e shown a supe io abili y o oli e
lea ex ac in educing pos p andial blood glucose, all being signi ican ly supe io
o placebo [
266
]. A me a-analysis o clinical ials ound ha phy os e ols educe
insulin esis ance, bu no enough o gene a e clinically signi ican imp o emen s
in glucose me abolism [
273
]. This is backed by
in i o
s udies ha demons a ed
inc eased exp ession le els and ac i a ion o di e en componen s o he insulin
ecep o signaling pa hway by phy os e ols [274,275].
2.
Ca dio ascula isk. In andomized, con olled, double-blind, and c osso e clinical
ials, adminis a ion o oleu opein and hyd oxy y osol [
276
]—as well as an oli e
lea ex ac [
277
]—signi ican ly educed
in i o
ascula s i ness and in e leukin-
8 p oduc ion in p ehype ensi e indi iduals and heal hy olun ee s, espec i ely.
Polyphenol adminis a ion in people wi h p e-diabe es o me abolic synd ome [
278
],
as well as in o e weigh o obese people [
279
], imp o ed bioma ke s o endo helial
dys unc ion. This imp o emen in endo helial unc ion was no associa ed wi h s im-
ula ion o angiogenesis [
124
]. In a double-blind, con olled, c osso e clinical ial,
hyd oxy y osol 7.5 mg b.i.d. inc eased an ioxidan enzyme exp ession and educed
le els o oxida i e s ess ma ke s [
280
]. A simila s udy—in which hyd oxy y osol
5 mg q.d and
25 mg q.d
was adminis a ed o 1 week— ound no di e ence in le -
els o bioma ke s o in lamma o y and edox s a us, angiogenesis, and li e heal h,
sugges ing ha his in e en ion equi es a longe exposu e ime [
281
].
In i o
, bo h
hyd oxy y osol and i s me aboli es lowe ed E-selec in, P-selec in, VCAM-1, ICAM-1,
and MCP-1 le els in TNF-
α
-s imula ed human endo helial cells, ye hyd oxy y osol
me aboli es in e es ingly exe ed a g ea e e ec han hyd oxy y osol a low concen-
a ions (
1µM
) [
282
]. A double-blind, con olled clinical ial in people wi h me abolic
synd ome showed how supplemen a ion o wo mino componen s (chlo ogenic acid
and lu eolin) imp o ed in ima-media hickness and low-media ed dila ion [
283
].
Rega ding FALs, policosanol is a mul i ace ed d ug wi h an iagg egan p ope ies
h ough di ec inhibi ion o h omboxane A2 syn hesis [
284
] and a lipid-lowe ing e ec
h ough he inhibi ion o choles e yl es e ans e p o ein (CETP) ac i i y, o e ing
p o ec ion o LDL pa icles om oxida ion [
285
,
286
]. In a double-blind, placebo-
con olled, pa allel clinical ial wi h ischemic hea disease pa ien s, policosanol 5 mg
b.i.d. wi h o wi hou aspi in 125 mg q.d. educed ca diac e en s and enhanced exe -
cise ole ance [
287
]. Clinical ials ha e shown ha policosanol 20 mg q.d. may ha e
less ad e se e ec s and be e e icacy han low-in ensi y s a ins and low-dose aspi in

Nu ien s 2022,14, 1440 17 o 36
in adul s wi h dyslipidemia [
288
,
289
]. A me a-analysis calcula ed an LDL-choles e ol
educ ion o
−
23.7% o each 12 mg o policosanol pe day [
290
], al hough o he clini-
cal ials ound no bene icial e ec s in mild hype choles e olemia [
291
]. Policosanol
educed LDL-choles e ol and iglyce ide le els, inc eased HDL-choles e ol le els,
and educed sys olic blood p essu e in a double-blind, placebo-con olled, and pa al-
lel clinical ial wi h women wi h p ehype ension [
285
]. In compa ison o a high- a
die , heal hy C57BL/6 mice ha we e ed a high- a die wi h 0.5% policosanol o
18 weeks de eloped a be e lipid p o ile, a educ ion in b own and whi e inguinal
adipose issue, a dis inc i e mic obio a p o ile, and enhanced lipolysis and he moge-
nesis [
292
], while, in a simila s udy, 60 mg/kg o ei he oc acosanol o policosanol
p o ec ed agains isce al a hype plasia and li e s ea osis [
293
]. Bene icial e ec s
o phy os e ols on LDL-choles e ol a e well es ablished, wi h a mean educ ion o
8–10% [
294
] and signi ican educ ions in ApoCII and ApoE [
295
]. An ex ensi e e-
iew o clinical ials wi h phy os e ols in ca dio ascula isk educ ion was published
elsewhe e [
126
]. The e is no de ini i e e idence on he impac o di iding he daily
phy os e ol in ake on choles e ol me abolism [296,297]; he e o e, u he s udies a e
needed o make ecommenda ions. The FDA has suppo ed he claim ha plan
s e ols and s anols—as pa o a die low in sa u a ed a and choles e ol—may educe
he isk o co ona y hea disease (CHD), ecommending an in ake o 1.3 g o mo e
pe day o plan s e ol es e s (a leas 0.65 g pe se ing) o 3.4 g o mo e pe day o
plan s anol es e s (a leas 1.7 g pe se ing) [
298
]. The phy os e ol con en o ypical
se ing sizes o EVOO is well below he 0.65 g h eshold. The associa ion be ween
phy os e ols and CHD is complex, and new e idence suppo s ha i may be di e -
en depending on he ood ma ix and demog aphics [
299
,
300
], clinical ac o s, and
gene ic ai s [
301
,
302
]. Plan s e ol oxida ion p oduc s (POPs) and hei consump ion
by non a ge popula ion g oups a e also a conce n. The EFSA has calcula ed ha
he app o ed maximum in ake o 3 g o plan s e ols pe pe son pe day may be
deemed ei he sa e o unsa e depending on i s oxida ion a e, which may depend
on he cooking me hod, i he esidual a is disca ded, and he cha ac e is ics o he
ood ma ix [
303
]. Ne e heless, s udies in animal models ha e shown ha some
POPs may ha e bene icial heal h p ope ies, such as lipid-lowe ing p ope ies ( ia
PPAR-
α
ac i a ion, induc ion o cy och ome P450, and inhibi ion o enzymes in ol ed
in hepa ic a y-acid syn hesis) [304].
3.
Obesi y. The e was a andomized, con olled, double-blind, and c osso e clinical
ial in which he addi ion o an oli e lea ex ac did no imp o e body composi ion
o ca dio ascula isk su oga es [
265
]. Oleu opein and hyd oxy y osol can educe
adipocy e hype plasia and hype ophy, by inhibi ion o adipogenesis- ela ed genes
in human cell lines [
305
,
306
] and s imula ion o mi ochond ial biogenesis- ela ed
genes in mu ine adipocy es [
307
]. When ed high- a die s, EVOO-supplemen ed mice
unde wen lowe weigh gains [
189
], and hey showed less me abolic, in lamma o y,
and mic obio a dis up ion [
308
], as well as mo e modes subcu aneous and isce al a
de elopmen —in ela ion o a highe basal ene gy expendi u e p opo ional o hei
weigh —which could be explained by a highe exp ession o Ucp genes in muscle and
isce al a [
309
]. Rega ding BMI educ ion, a me a-analysis o clinical ials calcula ed
s a is ically signi ican imp o emen s o ood en ichmen wi h phy os e ols and
phy os anols in dyslipidemic, o e weigh , and obese subjec s [310].
4.
Nonalcoholic a y li e disease (NAFLD). To ou knowledge, he e ha e been no in e -
en ion s udies in humans ha supplemen mino componen s in EVOO in pa ien s
wi h NAFLD. In humans, le els o si os e ols in he li e in adul s wi h NAFLD ha e
shown an in e se co ela ion wi h he deg ee o s ea osis and lobula in lamma ion by
li e biopsy [
311
] In animal models, li e damage induced by a high- a die was sig-
ni ican ly educed by supplemen a ion wi h EVOO [
312
,
313
], EPA + DHA [
314
–
316
],
DHA + EVOO [
317
] EPA + hyd oxy y osol [
318
–
321
], o hyd oxy y osol [
322
], show-
ing bene icial e ec s on in lamma ion, lipid con en , and hepa ocy e gene exp ession.
Nu ien s 2022,14, 1440 18 o 36
This e idence is mixed, as o he animal models ha e no demons a ed a posi i e
e ec o EVOO and i s phenolic compounds on he de elopmen o NAFLD [
189
] o
i s eg ession [
323
]. The bene icial e ec o EVOO agains NAFLD could be explained
by mi ochond ial p o ec ion—p e en ing he dec ease in ni a ed a y-acid le els
caused by a high- a die [
324
]— his abili y being di ec ly ela ed o i s phenolic con-
en [
325
]. In addi ion, EVOO’s lipid p o ile is low in linoleic acid (
ω
-6), p e en ing
a p oin lamma o y s a e due o an
ω
-6/
ω
-3 imbalance [
326
], wi h a high con en o
oleic acid (MUFA), ans o med in o oleyle hanolamide and s imula ing PPAR-
α
, and
α
-linolenic acid (PUFA), an
ω
-3 p ecu so ha igge s an is ea o ic, an ioxidan , and
an i-in lamma o y esponses in he li e ia mul iple molecula mechanisms [327].
5.
Cance . A nu igenomic s udy demons a ed ex i o ha oleu opein lea ex ac can
modi y he exp ession o genes in ol ed in oncogenesis in heal hy humans [
328
].
The e is an ex ensi e e iew o di ec an i umo al e ec s o oleu opein and hyd oxy-
y osol in
in i o
and ex i o models [
329
], which a e linked o
in i o
e idence o
he in a umo al ans o ma ion o oleu opein in o hyd oxy y osol [
330
]. Pleio opic
e ec s
in i o
and ex i o esul ing om combina ions o oleu opein, hyd oxy y osol,
and o he mino componen s wi h chemo he apeu ics and immunomodula o s, lead-
ing o d ug syne gism o a educ ion in undesi able e ec s, we e ho oughly e iewed
elsewhe e [
33
]. An ex ensi e e iew o he e ec s o EVOO and i s mino componen s
in p eclinical models o colon cance is also a ailable [
331
]. Oleu opein- ich EVOO
s imula ed
in i o
apop osis o colon cance cells and pe i oneal mac ophages in an
animal model [
332
], and a much mo e po en nanoencapsula ed mic oemulsion o
oleu opein was ecen ly de eloped and es ed in an animal model [
333
]. While he
addi ion o oleic acid induced DNA syn hesis and g ow h o he human colo ec al
adenoca cinoma cell line Caco-2, he subsequen addi ion o EVOO’s mino compo-
nen s p e en ed his e ec , e en inducing apop osis in he case o hyd oxy y osol
and maslinic acid [
330
]. Rega ding mechanisms o ac ion, oleu opein was able o
dec ease cell numbe and mo ili y in he human melanoma cell line A375—dec easing
hei glycoly ic capaci y (Wa bu g e ec )—a he expense o glucose anspo e
1 (GLUT-1)
, py u a e kinase M2 (PKM2), and monoca boxyla e anspo e 4 (MCT4)
inhibi ion [334].
6. Neu ological diseases. In a andomized clinical ial, an o al palmi oyle hanolamide
and lu eolin ex ac imp o ed he de ec ion h eshold, disc imina ion abili y, and
smell iden i ica ion in people wi h COVID-19 hyposmia [
335
]. Ne e heless, o al
lu eolin supplemen a ion in a quasi-expe imen al s udy was no supe io o placebo
a educing symp oms o Gul Wa Illness, a neu oin lamma o y condi ion [
336
].
Oleu opein has demons a ed neu op o ec i e e ec s in animal models o ce eb al
ischemia, ce eb al epe usion inju y, ageing, Alzheime ’s disease, Hun ing on’s dis-
ease, mul iple scle osis, Pa kinson’s disease, pe iphe al neu opa hy, spinal co d inju y,
and epilepsy [
337
,
338
]. Wi h espec o Alzheime ’s disease, oleocan hal was shown
o inc ease neu onal clea ance o
β
-amyloid by inc easing P-glycop o ein (P-gp) and
LDL ecep o - ela ed p o ein-1 (LRP1) le els in mouse b ains [
339
], while es o ing
he blood–b ain ba ie unc ion and educing neu oin lamma ion h ough inhibi ion
o PYD domain-con aining p o ein 3 (NLRP3) in lammasome and inducing au ophagy
h ough ac i a ion o he AMP-ac i a ed p o ein kinase/Unc-51-like au ophagy ac i-
a ing kinase 1 (AMPK/ULK1) pa hway [340].
7.
IBD. In con as o i s lipid p o ile, he mino i y componen s o EVOO may ha e
a bene icial e ec on IBD, al hough we ound no human in e en ion s udies. Ex
i o s udies in humans ha e poin ed o he abili y o oleu opein o educe in lam-
ma o y in il a e and in lamma o y ma ke s, imp o ing issue a chi ec u e [
341
,
342
].
In coli is animal models, oleu opein supplemen a ion dec eased mo ali y and im-
p o ed his opa hology by inc easing an ioxidan enzyme le els and Bcl2 exp ession
while educing p oin lamma o y cy okine and Bax exp ession [
343
], while EVOO
supplemen a ion imp o ed ec al bleeding [
344
] and he isce omo o esponse o
Nu ien s 2022,14, 1440 19 o 36
mechanical dis ension [
345
]. These bene icial e ec s may be enhanced by deli e ing
oleu opein ia lipid nanopa icles o ally [346]. To gain u he insigh in o his opic,
we poin he eade o an excellen e iew [347].
8.
Benign p os a ic hype ophy (BPH). In h ee andomized, double-blind, placebo-
con olled clinical ials,
β
-si os e ol demons a ed supe io i y in imp o ing sel -
epo ed soma ic and sexual symp oms, quali y o li e, peak u ine low, pos - oid
esidual olume, and plasma ee es os e one le els [
127
,
348
,
349
]. As possible ex-
plana o y mechanisms, his molecule educed 5
α
- educ ase ac i i y and p os a e
olume in a hams e model o BPH [
350
], while un ac iona ed oli e oil educed
p os a e olume in a mu ine model o BPH, a he expense o dec easing p os a ic
es os e one (T) and dihyd o es os e one (DHT) concen a ions [351].
9.
Os eopo osis. In a andomized, double-blind, 12 mon h clinical ial o pos menopausal
women wi h mild os eopo osis and no d ugs o diseases a ec ing phospho-calcium
me abolism, he addi ion o an o al oli e lea ex ac con aining 40% oleu opein o
1000 mg
o calcium ca bona e q.d main ained bone mine al densi y le els by DEXA
and inc eased os eocalcin in a sa e and well- ole a ed manne [
352
]. An ex i o s udy
in humans using oleu opein [
353
] and
in i o
s udies in mu ine models o os eopo o-
sis using EVOO and i amin D3 [
354
], oleu opein [
355
,
356
], and hyd oxy y osol [
357
]
ha e shown an an i-in lamma o y e ec —inhibi ing os eoclas ic ac i i y and educing
abecula bone loss—while in some cases also s imula ing os eoblas ic ac i i y. An ex-
cellen e iew o p e ious s udies indica ed ha EVOO’s bone p o ec ion is p obably
media ed by i s an i-in lamma o y capaci y [358].
10.
Rheuma oid a h i is (RA). In a pilo in e en ion s udy in newly diagnosed pa ien s,
he addi ion o 35 mg oleu opein o me ho exa e gene a ed he maximum educ ion
in ma ke s o cell damage, oxida i e s ess, and in lamma ion a 6 weeks [
359
]. In a
andomized clinical ial wi h a mean du a ion o app oxima ely 7 yea s, he addi ion
o an oli e lea , ig lea , and ui ex ac o me ho exa e imp o ed pa ien -pe cei ed
heal h s a us wi hou changing disease ac i i y scales by 16 weeks [
360
]. In a andom-
ized, c osso e clinical ial, he addi ion o EVOO and ish oil o disease-modi ying
d ugs (DMARDs) showed imp o ed pa ien -pe cei ed heal h s a us, inc eased unc-
ionali y, and lowe ed heuma oid ac o le els a 24 weeks compa ed o he addi ion
o ish oil o DMARDs [
218
]. All hese in e en ions we e sa e and well ole a ed.
In he TOMORROW coho , MUFA in ake was signi ican ly lowe in RA pa ien s,
while MUFA in ake ended o be an independen p edic o o disease emission [
361
].
In a c oss-sec ional s udy, he consump ion o oli e p oduc s in he usual die o
people wi h RA showed a good co ela ion and explana ion o a iance in p incipal
componen analysis wi h espec o hei calcula ed amoun o die e ical plan -de i ed
PUFAs. Howe e , he amoun o PUFAs was mos s ongly ela ed o he consump-
ion o walnu s and linoleic and alpha-linolenic acids, ac ing as possible con ounding
ac o s. In his s udy, consump ion o PUFAs was associa ed wi h a lowe deg ee o
disease ac i i y acco ding o Disease Ac i i y Sco e on 28 join s (DAS28), indepen-
den ly o an ibody posi i i y and wi h highe p o ec ion in mo e se e e o ch onic
o ms o he disease [362].
4. Discussion
EVOO has a pi o al ole in he MedD. Wi h i s well-balanced mix u e o oleic acid and
mino componen s, he culina y use o EVOO in he gene al popula ion may con ibu e
o he daily equi emen s o essen ial a y acids and an ioxidan body supply. Likewise,
whole EVOO, i s lipids, o mino componen s can be supplemen ed—in a sa e, e ec i e, and
well- ole a ed manne —in o i ied oods, o al, en e al, and in a enous pha macological
o mula ions in clinical nu i ion. Fu he mo e, die he apy wi h EVOO and he nu aceu ical
supplemen a ion o i s mino componen s cu en ly ha e a e y scien i ically sound a ionale
a e showing mul iple bene icial e ec s—in bo h in e en ion and mechanis ic s udies—in
impo an condi ions o public heal h, such as ca dio ascula heal h, lipop o ein me abolism,
Nu ien s 2022,14, 1440 20 o 36
and diabe es melli us. Cu en ly, p omising he apeu ic e idence—albei in di e en s ages
o de elopmen , and oo ea ly o ecommend speci ic EVOO-based die a y o nu aceu ical
in e en ions—is a ailable o condi ions such as obesi y, NAFLD, neu odegene a i e diseases,
os eopo osis, cance , and in lamma o y diseases, amongs o he s. Rega ding EVOO-based
o mula ions in clinical nu i ion, oleic acid-based ILEs al eady a e well es ablished pa en e al
o mula ions wi h widesp ead use in he clinical se ing. To ou knowledge, bo h o al and en-
e al oleic acid-based o mulas may acili a e me abolic con ol, al hough adequa ely blinded,
c osso e clinical ials wi h a high numbe o pa icipan s and an in en ion- o- ea analysis
a e needed o u he e alua e hei sa e y and e icacy in speci ic si ua ions.
Conside ing he a o emen ioned and possible u u e lines o esea ch, i would be
o high in e es o de elop in e en ion ials o u he e alua e he e ec o EVOO and
i s mino componen s on ha d endpoin s in high-impac clinical condi ions such as hea
disease, NAFLD, IBD, bac e ial in ec ions, o HIV. I would be o pa icula in e es o assess
he long- e m ca dio ascula sa e y and e ec s on hemos a ic and in lamma o y pa ame e s
o oleic acid-based o mula ions o en e al nu i ion o o al supplemen a ion—especially
wi h mino componen s om EVOO—in g oups wi h high ca dio ascula isk. Clinical
nu i ion could also bene i om u he s udies compa ing li e unc ion unde di e en
OO-based ILEs in a andomized ashion in di e en clinical popula ions. Las ly, sa copenia
and cogni ion in he elde ly a e e e -de eloping ields ha could bene i om well-planned
s udies assessing he impac o oleic acid-based o al and en e al nu i ion o mula ions, as
well as clinical ials designed o u he es he e icacy and ole abili y o EVOO’s mino
componen s in age- ela ed condi ions such as os eopo osis, cance , and demen ia.
5. Conclusions
EVOO has di e se bene icial heal h p ope ies and a well-es ablished ole in clinical
nu i ion. Mo e speci ically, he cu en e idence suppo s he use o whole EVOO in die
he apy and he supplemen a ion o EVOO’s mino componen s o imp o e ca dio ascula
heal h, lipop o ein me abolism, and diabe es melli us, as well as enough e idence o
he use—when a ailable—o oleic acid-based ILEs in pa en e al nu i ion. EVOO-based
nu i ional in e en ions ha e hus a shown e y p omising esul s in o he high-impac
clinical condi ions, bu mo e in e en ion s udies in humans a e needed in his case o
de elop speci ic ecommenda ions and g an new he apeu ic uses o EVOO h ough
di e en o mula ions and in speci ic clinical popula ions.
Supplemen a y Ma e ials:
The ollowing suppo ing in o ma ion can be downloaded a h ps:
//www.mdpi.com/a icle/10.3390/nu14071440/s1: Table S1. Composi ion o a y acids in EVOO
p oduced om di e en Medi e anean cul i a s; Table S2. Composi ion o some o he an ioxidan s
in EVOO p oduced om di e en Medi e anean cul i a s.
Au ho Con ibu ions:
Concep ualiza ion and me hodology, P.P.G.-L. and J.L.P.-C.; in es iga ion,
A.J.-S., A.J.M.-O. P.J.R.-R. and A.P.-G.; w i ing—o iginal d a p epa a ion, A.J.-S., A.J.M.-O., P.J.R.-R.
and A.P.-G..; w i ing— e iew and edi ing, A.J.-S.; supe ision and p ojec adminis a ion, P.P.G.-L.
All au ho s ha e ead and ag eed o he published e sion o he manusc ip .
Funding:
This a icle is pa o he R+D+i p ojec PID2019-107837RB-I00, unded by MCIN/AEI/10.130
39/501100011033/.
Ins i u ional Re iew Boa d S a emen : No applicable.
In o med Consen S a emen : No applicable.
Da a A ailabili y S a emen : No applicable.
Con lic s o In e es : The au ho s decla e no con lic o in e es .
Nu ien s 2022,14, 1440 21 o 36
Re e ences
1.
Commission Regula ion (EEC) No 2568/91 o 11 July 1991 on he cha ac e is ics o oli e oil and oli e- esidue oil and on he
ele an me hods o analysis. Consolida ed Tex . 01991R2568—EN—04.12.2016—031.005—1. O . J. Eu . Union 1991,248, 12–23.
2.
In e na ional Oli e Council. T ade S anda d Applying o Oli e Oils and Oli e Pomace Oils; COI/T.15/NC No 3/Re . 13; In e na ional
Oli e Council: Mad id, Spain, 2019; English e sion, O iginal: F ench e sion.
3.
Hippoc a es. T a ados Hipoc á icos: T a ados Qui ú gicos; Ma ía Dolo es, L.N., T ansla o ; In e na ional Oli e Council, G edos:
Mad id, Spain, 1993; Volume VII, ISBN 978-84-249-1610-7.
4.
Diosco ides, P.; Ga cía Valdés, M. Plan as y Remedios Medicinales: De Ma e ia Medica; Lib os I–III; Biblio eca Clásica G edos: Mad id,
Spain, 1998; ISBN 978-84-249-1958-0.
5.
Plinius Secundus, G. His o ia Na u al; Le as Uni e sales; Can ó, M.J., Ed.; Cá ed a: Mad id, Spain, 2002; ISBN 978-84-376-1958-3.
6.
Apa icio, R.; Ha wood, J.L. Handbook o Oli e Oil: Analysis and P ope ies, 2nd ed.; Sp inge : New Yo k, NY, USA, 2013;
ISBN 978-1-4614-7776-1.
7.
P eedy, V.R.; Wa son, R.R. Oli es and Oli e Oil in Heal h and Disease P e en ion, 1s ed.; Else ie : Ams e dam, The Ne he lands,
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