Health Benefits of Olive Leaf: The Focus on Efficacy of Antiglycation Mechanisms

Abstract

Olive leaves have been a therapeutic herbal agent for diseases for centuries. Olive leaves contain many health-beneficial nutrients and bioactive components. There is much evidence for the positive effects of the phenolic compounds they contain on health. The main active phenolic component in olive leaves is oleuropein, which can constitute 6%–9% of the leaf's dry matter and has been intensively studied for its promising results/effects on human health. In addition, olive leaf provides health benefits through bioactive components, such as secoiridoids, flavonoids, triterpenes, and lignans. The anti-inflammatory, antioxidant, anticancer, antidiabetic, and antihypertensive properties of bioactive components, especially oleuropein, are well known. In addition, various health benefits, such as neuroprotective effects and microbiota modulation, are also mentioned. In recent years, in vitro studies have shown that olive leaves and bioactive components from olive leaves may have antiglycation effects. Currently, it is thought that the components found in olive leaves have a direct or indirect antiglycation effect. It is thought that, their direct effects include reducing the interaction between sugars and amino acids, nucleic acids, and lipids and sequestering reactive dicarbonyl species, and their indirect effects include preventing the formation of advanced glycation end-products (AGEs) by reducing inflammation and oxidative stress. However, in vivo and clinical studies are needed to prove these mechanisms and understand how their metabolism works in the human body. This review examines the beneficial health effects of olive leaves and their potential antiglycation role.

INTRODUCTION

The olive tree comes from the evergreen tree genus of the Oleaceae family, which includes 24 genera and 900 species.¹ Olives have been used for centuries in traditional medicine as an herbal treatment to promote health and treat illnesses.² Olives, of which Mediterranean countries cultivate 98% of the world's production, are generally grown for their fruit; olive oil is obtained and consumed as table olives.^3,4 Olive byproducts are the remaining portions of the olive tree and the residue from the extraction process. Wastewater, olive leaves (OLs), and olive pomace are the main byproducts.⁴ Biophenols in OLs, 1 of the byproducts, vary depending on climate, type, and growing conditions.⁵ Biophenols in OLs differ from olive flowers, fruits, and branches.⁶

In recent years, there has been a surge in research on the pharmacological characteristics and therapeutic applications of the health-promoting biocomponents (particularly the phenolic compounds) in OLs.^7–10 It has been proven by numerous studies that especially the polyphenolic compounds it contains are potent antioxidants,¹⁰ free radical scavengers,¹¹ and have antitumor,¹² anti-inflammatory,¹³ antidiabetic,¹⁴ antihypertensive,¹⁵ and vasodilator properties.¹⁶ Furthermore, it has been suggested that they offer protective qualities against neurodegenerative illnesses, including Alzheimer's.^17,18 Several recent in vitro studies have provided evidence that they have an antiglycation effect in addition to these beneficial effects.^19–21

A collection of diverse substances, known as advanced glycation end-products (AGEs), are created after a series of nonenzymatic processes. They are produced physiologically and can be taken into the body through smoking and diet.²² Numerous illnesses, such as diabetes, cardiovascular disease, and neurodegenerative diseases, are linked to elevated levels of AGEs in the body.^23,24 For this reason, preventing the glycation of proteins (antiglycation effect) is essential to prevent and treat these pathologies. Both natural and synthetic sources can achieve the antiglycation effect. However, herbal sources are especially prominent for several reasons, such as having fewer side effects, consumer satisfaction, and being accessible and economical. There are many herbal antiglycation agents.^25,26 Olive leaves may be a potential and powerful antiglycation agent. Based on this information, after examining the relevant literature, this study was conducted to compile the effects of health-promoting biocomponents in OLs and potential mechanisms regarding the antiglycation effects.

METHODS

The search for studies was conducted using the PubMed, Web of Science, Science Direct, and Google Scholar databases through the University of Karabuk library using the following key words, individually or in combination: olive leaf, antiglycation natural agents, oleuropein, olive leaf extract, and health. Criteria for inclusion were intervention human or animal studies, observational studies, in vitro studies, and full-length research articles.

Olive Leaf Extract and the Bioactive Compounds It Contains

The olive's harvest period, origin, variety, and extraction method all substantially impact the chemical composition of OLs.^4,27 Various techniques are used to extract health-promoting biocomponents from OLs. The most commonly used methods are conventional solvent extraction methods with organic solvents (eg, ethanol and methanol) and water. Solvent extraction efficiency can be influenced by various variables, including the kind of solvent used, pH, temperature, number of extraction steps, solvent-to-solid ratio, and solid matrix particle size.⁴ However, these traditional methods have disadvantages, such as low efficiency and long extraction time.²⁸ New techniques for extracting bioactive chemicals from plant materials have recently been developed to overcome these restrictions. These techniques include homogenization, microwave assistance, ultrasound assistance, and high hydrostatic pressure. These modern techniques have a significantly smaller environmental impact, a much higher extraction efficiency, and a much lower solvent requirement.^29,30

Olive leaves contain many health-promoting nutrients and bioactive components. There is much evidence for the positive health effects of the phenolic compounds they contain.^31–33 The plants' pentose phosphate, shikimate, and phenylpropanoid pathways produce secondary metabolites known as phenolic chemicals. These substances belong to 1 of the most prevalent classes of phytochemicals. Additionally, they are crucial to the plants' morphology and physiology.¹¹ In OLs, phenolic chemicals are available in a wide variety of forms. These include secoiridoids, flavonoids, phenolic acids, and phenolic alcohols. The most prevalent phenolic chemicals are primarily vanillic acid, caffeic acid, hydroxytyrosol, tyrosol, rutin, verbascoside, luteolin, quercetin, oleuropein, demethyloleuropein, and ligstroside. In a study, phenolic compounds in OLs were evaluated, and 28 phenolic compounds were identified, including secoiridoids, flavonoids, triterpenes, and phenolic acids. More phenolic compounds were found in the study when organic solvents were used for extraction.³⁴ Another study conducted in Tunisia found that OLs contain bioactive molecules such as hydroxytyrosol, oleuropein. However, these molecules' antioxidant activity decreased by 64% and 88% following gastrointestinal digestion, respectively.³⁵ Oleuropein, which makes up 6%–9% of the dry matter of leaves and is the primary active phenolic component in OLs, has been the subject of extensive research due to its potentially beneficial effects on human health.^36–39

Many studies have been conducted on the health benefits of OLs, which are rich in phenolic compounds and beneficial oils, sugars, and other bioactive compounds. Antioxidant, anti-inflammatory, antimicrobial, antidiabetic, antiviral, and anticancer effects are the health benefits that stand out at first glance.^14,40–42

Secoiridoids

Terpenes, the precursors of several alkaloids, undergo secondary metabolism to form iridoids and secoiridoids.⁴³ The most abundant secoiridoid in OLs is oleuropein. Oleuropein is a class of phenol secoiridoids created when the 5-membered iridoid ring opens, along with demethyloleuropein, ligstroside, and uzenide.⁴⁴ Additionally, it is the primary compound in OLs, accounting for over 88%–94% of all phenolic compounds.⁴⁵ Either natural or exogenous β-glycosidase can readily convert oleuropein to glucose and oleuropein aglycone. Esterolysis of the final chemical yields hydroxytyrosol, a precious phenol molecule with a well-established bioactivity.²⁷ It is reported that oleuropein is found in much higher amounts in the leaves of olives than in their fruit. In a study, the phenolic contents of OLs were measured by the high-performance liquid chromatography (HPLC) method, and the most dominant phenolic compound was determined to be oleuropein. However, it was shown that oleuropein was decreased by 90% and 60% in simulated intestinal fluid and simulated gastric fluid, respectively.⁴⁶

The primary ingredient that gives olive plant fruits and leaves their bitter flavor is oleuropein. In particular, it is primarily responsible for the hypotensive effect of olive leaf extract (OLE). Hydroxytyrosol is found in much smaller amounts than oleuropein in OLs.⁴⁷ Hydroxytyrosol is formed from the hydrolysis of oleuropein and occurs in dry OLs at a rate of approximately 0.2 g/100 g.⁴⁸ Similarly, another secoiridoid that is relatively rare in quantity is oleasin.⁴⁹ Numerous studies have proven that all of these secoiridoids, especially because of their free radical scavenging activity, have neuroprotective, antimicrobial, anticancer, and anti-inflammatory effects.⁵⁰

Flavonoids

It is known that the phenolic composition of OLs is very complex and varies depending on the place where the trees are grown, the climate, and the ripening stage during the harvest and production process. In OLs, flavones and flavonols have been identified, including luteolin 7-O-glucoside, luteolin 7-O-rutinoside, luteolin 7,4′-O-diglucoside, luteolin, apigenin 7-O-glucoside, apigenin 7-O-rutinoside, and apigenin.⁵¹ The 2 main flavonoids found in Chemlali OL cultivars are apigenin 7-O-glucoside and luteolin 7-O-glucoside.⁵² Olive leaves contain 1.8% flavonoids. 0.8% of this is luteolin 7-glucoside.⁵³ Flavonoids can be found in both aglycone (quercetin, apigenin, luteolin, diosmetin) and glycosylated forms.⁵⁴

Other Bioactive Compounds

Phenolic compounds and other bioactive components, such as squalene, lignans, β-carotene, tocopherols, chlorophyll, triterpenes, and sterols, are present in OLs.⁵⁵ Because of their structural resemblance to estrogen, 17-β estradiol lignans are categorized as phytoestrogens. By attaching to estrogen receptors, they have an antiestrogenic impact that lowers the risk of hormone-related breast, ovarian, and prostate cancer.⁵⁶ Tocopherols belong to the tocochromanol family of compounds known as vitamin E. Olive leaf is an essential source of vitamin E. It has been shown that other phenolic compounds in the leaf can reduce the oxidized form of α-tocopherol to its active form. This confirmed that various health-beneficial compounds have a synergistic effect.^57,58 Apart from this, the squalene and sterols in OLs also show several health benefits, such as cellular signal transmission and prevention of lipid peroxidation.⁴³ The epidermis of olive fruit and leaf has been reported to contain various sterols and triterpenoids. Compared with the fruit, OLs have a higher triterpenoid concentration. Oleanolic acid is the main triterpene component and appears as a free acid in significant amounts (∼3% of the leaf dry weight).⁵⁹ There is evidence for antiviral, antibacterial, antifungal, anticariogenic, antiallergic, anti-inflammatory, hepatoprotective, gastroprotective, hypolipidemic, anti-atherosclerotic, and antidiabetic effects of these triterpenoids.^60–62

Olive Leaf Extract and Health

The effects of on health are generally attributed to the phenolic compounds they contain. Although the antioxidant properties^11,42,46 of these compounds are known, there is increasing evidence for their antiviral,^63,64 antimicrobial,⁶⁵ anti-inflammatory,^10,66 antidiabetic,⁶⁷ anticancer,⁴² and neuroprotective^68,69 effects. There is debate in the current literature about whether they have an antiglycation impact in addition to these properties.^19–21 Beneficial biocomponents found in OLs provide microbiota modulation, reduce malondialdehyde (MDA) and reactive oxygen species (ROS) levels, increase superoxide dismutase (SOD) levels (antioxidant); reduce tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), and nitric oxide (NO) levels (anti-inflammatory); increase apoptosis; reduce hypoxia-inducible factor-1α (HIF-1α) (anticancer); reduce blood sugar; and increase insulin secretion and glucose transporter type 4 (GLUT-4) expression (antidiabetic). They also have antimicrobial, antiviral, and antiglycative effects (Figure 1).

Antioxidant Effect

The antioxidant effect of OL is generally attributed to the oleuropein it contains. In a systematic review evaluating the antioxidant effects of oleuropein and OLE in animals, it was found that serum MDA levels decreased after supplementation and the synthesis of the antioxidant enzyme SOD increased dose-dependently.¹⁶ Olive leaf extract's antioxidant capacity was assessed using a cystic fibrosis cell culture.⁷ The study measured antioxidant activity by the number of reactive cell types (ROS). As a result, a significant decrease in intracellular ROS levels was observed in untreated cystic fibrosis cells at a concentration of only 0.12 mg/mL. In another in vitro study,⁶⁷ the antioxidant activity of OLE in 3 different genotypes was evaluated. Antioxidant activity was measured using the DPPH (2,2-diphenyl-1-picrylhydrazyl (DPPH) method) method, which reduced power and NO scavenging activity. At the end of the study, all 3 phenotypes showed a lower half-maximal inhibitory concentration (IC₅₀) (P ≤ .05) than quercetin as the standard (3.00 ± 0.01 μg/mL). Phenolic compounds have a strong antioxidant capacity, contributing to their high capacity to block NO generation. In the study evaluating the antioxidant effect of OLE in rats with chronic pancreatitis, a significant decrease was detected in the antioxidant parameters (serum SOD, MDA) of rats with pancreatitis given 200 mg/kg extract orally once a day for 3 weeks.⁶⁶ According to 1 study, oleuropein significantly and dose-dependently prevented low-density lipoproteins (LDLs) from being oxidized by copper sulfate.⁷⁰

As a result, in studies conducted on the antioxidant effect of OLE, it has been reported that oleuropein and hydroxytyrosol play a primary antioxidant role, have superoxide radical scavenging effects, and both compounds have a high ability to inhibit ROS because they have a catechol group.⁷¹ Elenolic acid derivatives were shown to have the lowest antioxidant activity ability.⁷² It is also reported that OLs can activate endogenous antioxidant systems in the body.⁷³

Anti-inflammatory Effect

It is known that OL has historically been used in traditional medicine as an anti-inflammatory plant. An in vitro study found that OLE had a significant inhibitory activity on TNF-α production and subsequent lipase stimulation in a concentration-dependent manner. When the bioactive components it contained were examined separately, it was found that only oleuropein had a significant inhibitory effect on the production of TNF-α at a concentration of 20 μg/mL. Other compounds showed no significant inhibitory effects at concentrations as high as 50 μg/mL, with the exception of gallic acid.⁵⁰ Fayez et al⁷⁴ examined the anti-inflammatory effect of OLE by inducing carrageenan-induced paw edema in rats. In a dose-dependent manner, OLE dramatically (P < .05) decreased paw inflammation. At the fifth hour of assessment, the extract at 200- and 400-mg/kg doses demonstrated the highest percentage inhibition, reaching 42.31% and 46.99%, respectively, compared to 63.81% achieved with the standard treatment. Moreover, the 400-mg/kg dose caused a significant decrease in the levels of COX-2 and NO, which was statistically equivalent to the concentration in the standard group. In the same study, anti-inflammatory activity was also evaluated in vitro. Olive leaf extract was determined to protect the erythrocyte membrane against heat-induced hemolysis. The effect of OLE on inflammation in the human placenta was evaluated in the study. Human placental tissues were incubated with control or oleanolic acid–enriched commercial OLE (0.1 or 1 mg/mL) for 6 hours at 37°C. At the end of the study, OLE administration dramatically decreased the release of interleukin (IL)-1β, IL-6, and IL-8 cytokines in human placental tissue culture. In addition, the applied treatment significantly reduced nuclear factor–κB (NF-κB) p65 protein expression in a human placental tissue culture.¹³ It has been shown that hydroxytyrosol derived from OL has unique anti-inflammatory effects by inhibiting protein kinase alpha (PKCα) and PKCβ1, hence reducing the induction of matrix metalloproteinase-9 (MMP-9) and COX-2 in activated human monocytes.⁷⁵ For 12 weeks, 46 adult participants were randomly assigned to receive capsules containing OLE or a placebo in a double-blind, placebo-controlled clinical research trial. At the end of the study, the subjects’ serum levels of C-reactive protein (CRP) and TNF-α had not changed significantly.⁷⁶

Antimicrobial and Antiviral Effect

Numerous human intestinal or respiratory pathogens, including Haemophilus influenzae, Moraxella catarrhalis, Salmonella typhi, Vibrio parahaemolyticus, Staphylococcus aureus, Vibrio cholerae, and Vibrio alginolyticus, are inhibited or delayed in their rate of development by hydroxytyrosol and oleuropein.⁶⁵ Olive leaf extract exhibits vigorous antiviral activity with regard to interfering with the generation of essential amino acids in viruses and preventing them from cleaving, budding, or assembling at the cell membrane. It also can enter infected cells and directly halt viral reproduction.⁴ Studies generally emphasize that oleuropein is an important compound responsible for the antimicrobial effect. The precise process of oleuropein antibacterial action is still not fully understood. However, some authors have suggested that it is due to the ortho-phenolic system (catechol).⁷⁷ The antibacterial activity of commercial OLE (abundant oleuropein) against methicillin-resistant S aureus, Helicobacter pylori, and Campylobacter jejuni was recently demonstrated by Sudjana et al.⁷⁸ The authors also demonstrated how these extracts specifically lower the amounts of H pylori and C jejuni, which control the composition of the intestinal flora. In another study, OLE did not show bactericidal and bacteriostatic activity against Escherichia coli and Staphylococcus typhimurium.⁷⁹ The effect of OLE against Campylobacter spp, which is mainly influential in the formation of gastroenteritis, was evaluated. An extract rich in hydroxytyrosol and hydroxytyrosol glycosides (14.708 mg/100 g) showed potent antibacterial activity and reduced bacterial growth from 4.12 log–colony-forming units (-CFU)/mL to 8.14 log-CFU/mL, depending on the strain. At low doses (0.1–0.25 mg/mL), the primary component that inhibited the growth of Campylobacter strains was hydroxytyrosol.⁸⁰

Antidiabetic Effect

Olive leaf is known as a traditional antidiabetic and antihypertensive herbal medicine. It is an antidiabetic herbal treatment agent, especially in Europe.¹ The study determined that luteolin and oleanolic acid in OLE prevented postprandial blood sugar increases in diabetic rats. This effect was reported due to its inhibitory effect on intestinal and/or salivary amylases.¹ It has been emphasized that oleuropein also has an antidiabetic effect and that it achieves this effect through the mechanisms of affecting glucose-induced insulin release and increasing peripheral glucose uptake.⁸¹ A study conducted with diabetic rabbits found that, after 16 weeks of treatment with 20-mg/kg body weight oleuropein, blood glucose was significantly reduced compared with the control group.⁸¹ In an in vitro study, oleuropein was observed to cause 10%–20% increases in insulin-secretion levels at 30 μM. It was also determined that ligstroside, an analog of oleuropein, protected the glucose-induced insulin secretion function with a potency similar to that of oleuropein. The other analogs, hydroxytyrosol and tyrosol, did not affect the stimulation of insulin secretion.⁸² Hydroxytyrosol was found to downregulate GLUT4 gene expression. This was reported to result from hydroxytyrosol inhibiting peroxisome proliferator activating receptor gamma (PPARγ) and Ccaat-enhancer-binding proteins alpha (C/EBPα).⁸³

In a study conducted with diabetic rats, 20 mg/kg hydroxytyrosol per day was administered intraperitoneally to rats for 8 weeks. At the end of the study, serum glucose levels were significantly lower than those of the control diabetic group.⁸⁴ Although the positive effects of hydroxytyrosol directly on insulin release are still debated, it has been reported that it significantly inhibits the formation and cytotoxicity of amylin aggregates in INS-1β cells. In this case, it effectively preserves pancreatic β-cell function and indirectly has a positive effect on preventing the progression of diabetes pathogenesis.⁸² In a review study, it was reported that hydroxytyrosol had a positive effect on insulin release by regulating calcium channels.⁸⁵ In an in vivo study conducted directly with OLE, serum glucose and glycated hemoglobin (HbA1c) levels of the diabetic group given 200 mg/kg extract by intragastric gavage for 21 days were not found to be different from those in other groups.⁸⁶ In another recent study, 2.0% OL powder was added to the standard diet of diabetic rats. After 4 weeks, diabetic rats fed the OL powder diet showed a significant 53.0% decrease in serum glucose level compared with the untreated group. This decrease was higher compared with the group using metformin.⁸⁷ Oral administration of 50 mg/kg oleuropein in rats fed a high-fat diet for 8 weeks improved glucose tolerance and reduced hyperinsulinemia. It also revealed that the expression level of phosphorylated AKT (p-Akt), insulin receptor substrate 1 (IRS1), and GLUT-4 was significantly increased in liver and adipose tissues after oleuropein supplementation. In addition, the expression of IRS1 in the pancreas was significantly improved.⁸⁸

Anticancer Effect

Evidence exists for the antitumor effects of hydrophilic phenols, hydrocarbons, triterpenes, and sterols found in OLs.^89,90 An in vitro study evaluated the anticancer effect of hydroxytyrosol in acute human leukemia T cells (Jurkat, HL60). Apoptosis and cell cycle analyses revealed hydroxytyrosol's antiproliferative effect, reducing the percentage of dividing cells and increasing apoptosis.⁹⁰ In another study, MCF7 and T-47D breast cancer cell treatment with 100 μM hydroxytyrosol or 150 μM oleuropein significantly reduced the cells' viability. This revealed that both cell lines were more sensitive to treatment with hydroxytyrosol than oleuropein.⁹¹ Olive leaf phenolic compounds are reported to cause significant apoptosis in cancer cells by regulating the NF-κB activation cascade.⁹² It has also been reported that oleuropein suppresses the proliferation of human colorectal cancer cells by inhibiting the expression of HIF-1α and upregulating the expression of p53 protein.¹² The effects of oleuropein on cancer through its microRNA (miRNA) editing ability were evaluated. It was observed that oleuropein increased the expression levels of miR-125b, miR-16, miR-34a, p53, p21, and TNF receptor superfamily member 10b (TNFRS10B) and decreased the expression levels of bcl-2, mcl1, miR-221, miR-29a, and miR-21. The results showed that oleuropein could cause apoptosis by reducing the expression of anti-apoptotic genes and onco-miRs and raising the expression of proapoptotic genes and tumor suppressor miRNAs.⁹

Effect on Microbiota

While evidence for the effects of olive oil consumption on the microbiota is abundant in the literature, little is known about the specific bioactive components in OL.¹⁸ Hydroxytyrosol and tyrosol are primarily absorbed in the small intestine. Oleuropein reaches the colon essentially unchanged, where the microflora rapidly breaks it down to synthesize hydroxytyrosol.⁹³ Lactic acid bacteria, such as Lactobacillus and Bifidobacterium species, preferentially break down oleuropein in vivo. These bacteria typically use oleuropein as a carbon source and profit from its metabolism.⁹⁴ Han et al's study⁹⁵ showed that hydroxytyrosol administration in mice increased the relative abundance of Firmicutes and Lactobacillus and decreased the relative abundance of Bacteroidetes. In 1 study, hydroxytyrosol increased Lactobacillus concentration but did not change the Firmicutes-to-Bacteroidetes ratio. These effects of hydroxytyrosol indicate that it may help control intestinal dysbiosis.⁹⁶ In addition to this positive effect of hydroxytyrosol on dysbiosis, reducing Parabacteroides and increasing Firmicutes is also important for reducing oxidative stress and inflammation.⁹⁵ Not only hydroxytyrosol but also oleuropein has effects on the microbiota. One study found that the administration of oleuropein at a dose of 200 mg/kg for 15 weeks modulated the gut microbiota at the phylum level, increasing the relative abundance of Verrucomicrobia and Deferribacteres and decreasing the relative abundance of Bacteroidetes. This modulation was reportedly therapeutic, especially for type 2 diabetes.⁹⁷ Vezza et al⁹⁸ found that OLE applied for 5 weeks could prevent obesity-related dysbiosis in mice. In a study with diabetic rats, a mixture of OLE and ginger rhizomes increased overall bacterial diversity and the Firmicutes/Bacteroidetes ratio in both healthy and diabetic rats. It also decreased the relative abundance of Clostridium and Bacteroides while increasing the relative abundance of Lactobacillus and Prevotella in healthy rats. These results showed that OL benefits diabetes and dysbiosis management by increasing short-chain fatty acid synthesis, which is essential for intestinal health.⁸

Potential Antiglycation Effect

Glycation is a series of chain reactions that occur when the carbonyl group of the reducing sugar reacts nonenzymatically with the amino group of the protein, lipid, or nucleic acid.²¹ Glycation occurs at cellular and extracellular matrix levels, forming AGEs.⁹⁹ Glycation happens physiologically as a result of aging and several diseases. However, the biological significance of AGEs comes from their accumulation in vivo. Through irreversible cross-linking, AGEs preferentially attach to arginine and lysine residues in proteins to change their structure and function. This is associated with many pathologies, including diabetes and neurodegenerative diseases.¹⁰⁰ Apart from the AGEs synthesized endogenously in the body, the relationship of dietary AGEs with health is now well known.^24,101,102 It seems possible to inhibit excess dietary AGEs with natural nutritional components.^103,104 Currently, various antiglycation mechanisms have been suggested, particularly for polyphenols. These mechanisms involve trapping reactive dicarbonyl species, which inhibits glycoxidation events and stops the glycation process in its early or further phases.^20,105 It has been reported that the health-beneficial polyphenols found in OLE may have a positive effect, especially on dietary AGE intake.¹⁹ In an in vitro study, the effect of OLE on the formation of AGEs in a hepatic cell line (HepG2) was evaluated. The extract concentrated in hydroxytyrosol showed the highest anti-AGE effect in different glycation models (IC₅₀: 0.25–0.29 mg/mL). In addition, the extract significantly reduced the production of Arg pyrimidines (26%) and protein carbonylation (21%) in a hepatocyte cellular carbonyl stress model generated by methylglyoxal (MGO).²¹ Another study evaluated the in vitro antiglycation effect of aqueous and methanolic OLE. In the bovine serum albumin (BSA)–ribose system, methanolic OLE prevented the development of fluorescent AGEs, but aqueous OLE had no effect in the BSA-fructose or BSA-ribose systems. Additionally, the AGE inhibition ability of the phytochemicals contained in OLE was examined. The inhibitory effect of luteolin and luteolin-4′-O-β-d-glucopyranoside was dose-dependent, while the inhibitory effect of luteolin-7-O-β-d-glucopyranoside, hydroxytyrosol, and oleuropein was relatively small and insignificant. It was thought that oleuropein did not have an anti-AGE effect at the dose used in the study. The inhibitory effect of luteolin-4′-O-β-d-glucopyranoside (having a catechol group) is more significant than that of luteolin-7-O-β-d-glucopyranoside, which may be due to glycosylation of the hydroxyl group at the C-7 position and methylation of the 4′-hydroxyl group of flavonoids, or confirms that glycosylation reduces antiglycation activity.¹⁹

A study on the inhibition of AGE content in heat-treated foods evaluated the antiglycative effect of hydroxytyrosol and OLE in wheat flour biscuits. Gallic acid and quercetin were used as reference antiglycation agents. A significant decrease in the 3-deoxyglucosone (3-DG) content of biscuits formulated with hydroxytyrosol was observed compared with the control. Additionally, hydroxytyrosol inhibited the formation of free fluorescent AGEs by 28.8%, and this rate was below 10% in biscuits containing gallic acid and OLE. The free carboxymethyllysine (CML) content in the biscuit with added OLE decreased by 42.16% compared with the control biscuit. The results showed that the phytochemicals contained in OLE may be inhibitory natural components for AGEs.²⁰ In another recent study, the antiglycation effects of samples of OLs created using different extraction techniques were examined. The ability of the oleuropein-enriched extract to inhibit fluorescent AGEs was higher than with pure OLE, pure hydroxytyrosol, and aminoguanidine.¹⁰⁶ A study examining the antiglycation effects of commercial nutritional supplements determined that commercial OLE containing 4.4 mg/mL oleuropein and 250 μg/mL hydroxytyrosol was the most effective AGE inhibitor with the lowest IC₅₀.¹⁰⁷

Although there are few studies on direct OLE or biocomponents are isolated from this extract, there are data on the antiglycation effects of beneficial biocomponents in OLs. The antiglycative effects of phytochemicals such as triterpene, phenolic acids, and quercetin provide important indications that OL can also be a powerful antiglycation agent.^26,108–110

When the relevant literature is examined, it is thought that OLE exerts its potential antiglycation effects through indirect and direct effects. In its direct effect, it reduces the interaction between reducing sugar and amino acids, nucleic acids, and lipids and traps reactive dicarbonyl species; and in its indirect effect it prevents the formation of AGEs by reducing inflammation and oxidative stress (Figure 2).

As shown in Figure 2, several factors, such as a Western diet, smoking, inflammatory diseases, and aging, can affect the body's AGE pool. A potential antiglycating agent to combat increased levels of AGEs is OL. Components in OL can have direct and indirect antiglycation effects. While the direct effect prevents the combination of the reducing sugar and the amino group, the indirect effect is to prevent the formation of AGEs by reducing inflammation and oxidative stress.

CONCLUSION

Since ancient times, OL has been used in traditional medicine to prevent and/or treat many diseases. Its anti-inflammatory, antioxidant, neuroprotective, anticancer, and antidiabetic effects are well known, especially with its bioactive components, such as phenolic compounds, secoiridoids, and triterpenoids. In addition, it has been thought to have an antiglycation effect in a few limited in vitro studies. Although it is generally thought that the antiglycation effect is due to its antioxidant properties and ability to capture reactive dicarbonyl species in vivo, studies are also needed to understand the mechanisms. In particular, understanding how the digestion, absorption, and metabolism of bioactive components in the body will affect the inhibition of dietary AGEs is important for the prevention and/or treatment of various pathologies.

Author Contributions

B.D. and G.S. designed the research. B.D. conducted the research and wrote the manuscript. B.D. and G.S. examined the initial draft critically and revised, reviewed, and approved the final manuscript.

Funding

No external funding supported this study.

Conflicts of Interest

None declared.

REFERENCES