Quercetin is the most widely studied flavonoid, primarily derived from apples, berries, tomatoes, onions, and lettuce. The hydrophilic glycoside (quercetin glucosylation) is the primary form of quercetin in plants that are not absorbed by intestinal cells directly. In intestinal epithelial cells, quercetin glycosides undergo various changes and are a part of crucial enzymatic reactions, such as hydrolysis, methylation, and sulfonylation by specific transferases and glucuronidation. Therefore, quercetin glycosides are absorbed and used by intestinal epithelial cells. Quercetin is metabolized in the intestine, and its methylated metabolite isorhamnetin is the major form found in serum (Shi et al., 2019). Quercetin exhibits anti-inflammatory, antioxidant, and antimicrobial properties and is used as a dietary supplement at a safe dose of 1 g/day with approximately 60% absorption (Yang et al., 2020; Deepika and Maurya, 2022).

In 1994, Hanasaki et al. (1994) reported that quercetin had the most robust rate of scavenging active oxygens among the flavonoids. Quercetin contains four hydroxyl groups; thus, it can act as an antioxidant and directly scavenge free radicals that are produced in the body. Quercetin treatment primarily regulates glutathione (GSH) levels to enhance antioxidant capacities. Chronic and high quercetin intake significantly increases the ratio of GSH/oxidized GSH in the liver, reduces malondialdehyde (lipid peroxidation marker) levels in the liver, adipose tissues, and small intestine, induces antioxidant enzyme expression, including glutathione peroxidase 1, catalase (CAT), and superoxide dismutase (SOD), by activating the liver nuclear factor E2-related factor 2 (Nrf2) pathway (Kobori et al., 2015). Geng et al. (2019) used the Werner syndrome (WS) human mesenchymal stem cells (hMSCs) to screen natural products and reported that quercetin could alleviate aging in hMSCs by promoting self-renewal and differentiation abilities of WS hMSCs and restoring the heterochromatin structure. In vitro, quercetin can promote oocyte maturation and early embryonic development in humans and aged mice by clearing mitochondrial reactive oxygen species (ROS), reducing apoptosis, and improving autophagy (Cao et al., 2020). Quercetin prolongs the lifespan and enhances motility in aged Caenorhabditis elegans with heat-stress tolerance by regulating insulin-like signaling and the p38-mitogen-activated protein kinase (MAPK) pathway (Sugawara and Sakamoto, 2020). Furthermore, quercetin chelates metal ions and catechol in its structure is an important antioxidant. Studies show that quercetin inhibits lipid peroxidation by binding to Fe²⁺ and attenuating iron overload and oxidative damage in chronic ethanol hepatotoxicity (Tang et al., 2014). Despite quercetin is known as a powerful antioxidant, studies have demonstrated that quercetin treatment may result in pro-oxidant, neurotoxic and cytotoxic effects depending upon certain experimental conditions (e.g., time, dose, formulation, etc.) and the pro-oxidant properties seem to be dose-dependent (Prochazkova et al., 2011). One study evaluated the effects of quercetin stabilized by microencapsulation at two doses (10 mg/kg and 100 mg/kg) on the diabetic rats. After 60 days, high-dose administration of quercetin (100 mg/kg) further aggravated the diabetic condition and resulted in harmful effects on healthy rats, pointing to a pro-oxidant activity. However, low-dose administration of quercetin (10 mg/kg) gave rise to antioxidant and protective effects on nitrergic innervation and interstitial cells of Cajal, nitrergic neurons, macrophages and oxidative/antioxidant status in diabetic rats (Vieira-Frez et al., 2020). A study investigated the potential antioxidant and prooxidant effects of quercetin on cultured non-small lung cancer A549 cells. It demonstrated concentration-dependent effects of quercetin in vitro, including augmentation of thiol content, total intracellular capacity at low quercetin concentrations (0.1–10 μM) and decrease in thiol content, total antioxidant capacity, cell proliferation, and induction of cell apoptosis and necrosis at higher concentrations of the quercetin (>50 mM) (Robaszkiewicz et al., 2007).

Quercetin has been regarded as an antiaging compound because of its long-term anti-inflammatory properties. The anti-inflammatory and antiallergic properties of quercetin have been proven to treat respiratory and food allergies (Escribano-Ferrer et al., 2019). It has been shown to effectively lower the levels of inflammatory cytokines in the lipopolysaccharide (LPS)-induced inflammatory RAW 264.7 cells (Kang et al., 2022) and rat intestinal epithelial (IEC-6) cells via suppressing NF-κB activation in vitro (Cai et al., 2021). Quercetin administration in diabetic rats also effectively decreases the levels of serum C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), blood glucose, and inflammatory cytokines by enhancing AKT phosphorylation, inhibiting nuclear factor-kappa (NF-κB) levels, and reducing inflammation-induced hyperlipidemia (Hosseini et al., 2021). Elbe et al. (2016) reported that quercetin reduces the levels of inducible nitric oxide synthase (iNOS) and IL-12 in renal diseases and ameliorates the excessive accumulation of extracellular matrix and interstitial fibrosis by antagonizing NF-κB and TGF-β1/Smad2/3 signaling activation. Organ dysfunction has recently been reported to be closely related to coronavirus disease (COVID-19) progression, which may cause acute kidney injury (AKI). Quercetin has also been reported to treat COVID-19-induced AKI, which can be attributed to the anti-inflammatory properties of macrophage polarization and the inhibition of NF-κB p65 and interferon regulatory factor 5 (Diniz et al., 2020). The inhibition of proinflammatory cytokines such as IL-6, TNF-α, and IL-1β and inflammatory mediators such as catalase and nitric oxide underlie the anti-inflammatory effects of quercetin.

Several studies have found that quercetin has a spectrum of antimicrobial properties; it has significant inhibitory effects on both fungi and bacteria mainly because it can improve cell permeability, reduce enzyme activity, destroy the cell wall structure, and inhibit nucleic acid synthesis (Wang et al., 2018; Yang et al., 2020). Furthermore, in terms of the potential harm with antibiotic abuse, quercetin directly affects various microorganisms in the intestine. It can effectively enhance the diversity of gut microbiota and restore its composition after antibiotic treatment (Shi et al., 2020). Quercetin treatment also significantly improves the morphology and thickness of intestinal mucosa along with enhancing the length of the villi and glands. The levels of D-lactate and the activity of diamine oxidase were significantly decreased in the serum of quercetin-treated mice. Thus, quercetin may act as a prebiotic to combat gut dysbiosis and restore intestinal permeability. Quercetin is also a potent inhibitor of β-catenin/T-cell factor (TCF) signaling in colorectal cancer (Park et al., 2005). It has also been reported to inhibit the proliferation of colorectal cancer cells by regulating the Wnt/β-catenin signaling pathway (Shan et al., 2009). In conclusion, quercetin exhibits anti-inflammatory, antioxidant, and antimicrobial properties. It primarily regulates glutathione levels, reduces malondialdehyde levels, induces antioxidant enzyme expression, and can promote oocyte maturation. Quercetin can alleviate aging in mesenchymal stem cells and inhibit the proliferation of colorectal cancer cells. However, its effectiveness varies with experimental conditions and doses.

Luteolin is a natural flavone originally isolated from Reseda luteola (Chen Y. et al., 2022). It is found in the leaves of many medicinal plants and foods, such as parsley, celery, broccoli, rosemary, cardamom, anise, and dandelion (Jia et al., 2015). Although luteolin is a minor component in daily nutrition, accumulating data suggest it has numerous health benefits including potent antioxidant, anti-inflammatory, and antiallergic properties.

Luteolin can prevent or reduce photoaging, which is collagen and elastin degradation, leading to wrinkled skin. It reduces the solar ultraviolet-induced release of proinflammatory cytokines (IL-6, TNF-α, and IL-20) from keratinocytes and fibroblasts, which may be attributed to its radical scavenging and antioxidant properties. Cyclooxygenase 2 (COX-2) is crucially involved in ultraviolet radiation B-induced acute inflammation by catalyzing the production of the prostaglandin precursor prostaglandin E2 (PGE₂), and luteolin can inhibit the syntheses of COX-2 and PGE₂. Further in vitro and in vivo studies indicate that luteolin can also modulate the SIRT3/ROS/MAPK signaling pathway to prevent skin photoaging (Mu et al., 2021), which indicates that luteolin may prevent the development of skin aging and skin cancer (Gendrisch et al., 2021). Luteolin has protective effects against vascular inflammation and inhibits monocyte binding to endothelial cells by suppressing the IκBα/NF-κB pathway (Jia et al., 2015). Luteolin pretreatment inhibited the formation of BV-2 microglia after LPS stimulation. In vivo results suggest that the consumption of luteolin improves spatial working memory and cognition by reducing microglia-associated inflammation in the hippocampus (Jang et al., 2010). Luteolin can also inhibit the transcription (STAT) signaling pathway to modulate the interferon-gamma-induced microglial CD40 expression (Rezai-Zadeh et al., 2008). With the progression of age, mitochondrial function, morphological content, and oxidative phosphorylation abilities appear impaired (Koopman et al., 2012). In Caenorhabditis elegans models, luteolin treatment improves mitochondrial dysfunction in primary neurons and enhances locomotory activities. It can also be used to regulate mitochondrial endoplasmic reticulum coupling and has potential therapeutic effects on various aging-related diseases (Naia et al., 2021). Luteolin has also been reported to increase the deacetylation of SIRT6, regulate the expression of other SIRTs and Forkhead box O3a (FOXO3a) in human monocytes, and suppress ROS production under hyperglycemic conditions (Kim et al., 2017; Akter et al., 2021).

Catechins are flavanols with green tea as the main component, which is a nonfermented tea extracted from the leaves of Camellia sinensis (Ouyang et al., 2020). Other foods or botanical drugs also contain these polyphenolic compounds, such as apples, cacaos, berries, persimmons, and grapes. Many studies have indicated that catechins have multiple health-related functions due to their antioxidative properties, anti-inflammatory properties, lipid metabolism, energy metabolism, autophagy, and immunoregulatory effects (Ouyang et al., 2020; Chen Y. et al., 2022). Catechins include EGCG, epigallocatechin, epicatechin, epicatechin-3-gallate, gallocatechin gallate, and gallocatechins. EGCG is the major and most abundant catechin (Khan and Mukhtar, 2018).

Early studies have revealed that EGCG can extend the lifespan of healthy rats by reducing damage to liver and kidney function (Niu et al., 2013). More recent studies indicate that EGCG significantly prolongs the lifespan of high-fat-diet-induced obese rats by improving free fatty acid metabolism, inflammation, and oxidative stress. It can directly increase the longevity of mRNA and protein levels of Sirt1 and FOXO1 and decrease the expression of NF-κB, acetyl-CoA carboxylase, and fatty acid synthase (Yuan et al., 2020). Consistent with these findings, green tea extracts can reverse the fat-induced mortality in Drosophila melanogaster, and EGCG can enhance the fitness and lifespan of Drosophila (Li et al., 2008; Wagner et al., 2015). EGCG supplements improve the oxidative stress in PC12 cells induced by 1-methyl-4-phenyl-pyridine via the SIRT1/PGC-1α signaling pathway, which provides a novel target to prevent and treat Parkinson’s disease (Ye et al., 2012). All green, puer, and black tea extracts can increase the lifespan of Caenorhabditis elegans, postpone beta-amyloid (Aβ)-induced progressive paralysis in transgenic worms with Alzheimer’s disease (AD), and improve the oxidative stress tolerance of worms (Fei et al., 2017). Green tea extracts have been reported to increase the number of SH-groups leading to reduced GSH accumulation in the plasma, restrained ROS generation, and improved antioxidant enzyme activities (Bártíková et al., 2015). The antioxidative effects of catechins may not be entirely manifested in SOD scavenging. Epicatechin intake can enhance Nrf2 and heme oxygenase-1 (HO1) protein levels in the nuclei of cortical neurons in mice (Wu et al., 2006), and activate the phosphatidylinositol-3-kinase/protein kinase B (PI3K)/AKT and extracellular-regulated kinase (ERK) signaling pathways in hepatocytes (Si and Liu, 2014). EGCG can also prevent stroke damage by activating Nrf2 and HO1 productions. Green tea polyphenols ameliorate early renal damage induced by a high-fat diet via the ketogenesis/SIRT3 pathway (Yi et al., 2017).

EGCG is regarded as a healthy and natural dietary supplement. However, EGCG also exhibits significant pro-oxidant effects under high-dose conditions (Ouyang et al., 2020). Low doses (50–300 µM) of EGCG can extend the lifespan of Caenorhabditis elegans and Drosophila, but high doses (1,000 μM) are harmful to longevity; this is because of excessive ROS accumulation and DAF-16 (a forkhead transcription factor) activation. Theanine is known to alleviate the adverse effects caused by high EGCG doses (Peng et al., 2021). The pro-oxidant properties of EGCG can be beneficial or harmful. Auto-oxidation of EGCG generates substantial ROS, which may induce apoptosis and inhibit the growth of adipocytes in cancer cells, leading to anticancer and antiobesity properties (Ouyang et al., 2020). Taken together, EGCG has antioxidant and anti-inflammatory properties and can improve lipid and energy metabolism, autophagy, and immune system regulation EGCG can also ameliorate early renal damage and prevent stroke damage. However, high-dose EGCG can exhibit significant pro-oxidant effects, leading to potential toxicity. Therefore, although green tea extracts and EGCG have many health benefits during aging, further studies are required to determine their potential toxicity, optimal doses, and applications in the field of antiaging.

Resveratrol (3, 5, 4′-trihydroxystilbene) is a polyphenol subgroup widely found in various foods and beverages consumed daily, including grapes, peanuts, pomegranates, blueberries, cocoa, and red wine. Polygonum cuspidatum is the plant source that is richest in resveratrol. Resveratrol was originally separated in 1940 from the roots of Veratrum grandiflorum, a Chinese herbal medicine, and was identified as the most important functional red wine ingredient in 1992 (Perrone et al., 2017). Studies have revealed that resveratrol exhibits a variety of pharmacological activities such as antioxidant, anti-inflammatory, antimicrobial, immunomodulatory, and neuroprotective properties; moreover, it combats age-related degenerative diseases (Diepvens et al., 2007; Perrone et al., 2017; Santhiravel et al., 2022). Considering these multiple properties, studies on the application of resveratrol as a nutritional supplement are gradually increasing.

Resveratrol is a strong antioxidant and can protect cell biomolecules from oxidative damage by directly scavenging ROS and enhancing glutathione s-transferase (GST) levels (Truong et al., 2018). Resveratrol attenuates acute kidney inflammation and oxidative stress by activating the Nrf2 pathway, restoring antioxidant capacity, reducing apoptosis, and inhibiting the NF-κB pathway and caspase cascade (Uddin et al., 2021). Dietary resveratrol has also been suggested to ameliorate H₂O₂-induced liver injury in tilapia along with reducing the lipid peroxidation level, inflammatory response, and immunotoxicity. Resveratrol treatment also enhances the HO-1, NAD(P)H:quinone oxidoreductase 1, GST, and IL-10 levels and decreases the inflammatory cytokine levels of IL-1β, TNF-α, and IL-8. It can modulate the Nrf2 and TLR2/MyD88/NF-κB signaling pathways (Boccellino and D'Angelo, 2020; Uddin et al., 2021). Evidence suggests that resveratrol can be considered a prebiotic to improve gut microbiota-related disorders in age-related diseases. The oral administration of resveratrol can improve glucose homeostasis in high-fat-diet-induced obese mice (Sung et al., 2017). Furthermore, obese mice receiving fecal microbiome transplants from resveratrol-fed donors have shown an improvement in metabolic syndrome within 11 days. Resveratrol fecal transplants also decrease inflammation in the colons of obese individuals (Kim et al., 2018).

Resveratrol is an activator of SIRT1, regulating cellular energy metabolism and mitochondrial homeostasis. AMPK has been reported to be an attractive target for extending a healthy lifespan, and studies show that resveratrol can activate AMPK and possesses antiobesity abilities (Si and Liu, 2014). Mice that were fed a high-fat diet containing 0.1% resveratrol showed brown-like adipocyte formation in white adipocyte tissues, along with an increased expression of uncoupling protein 1, PR domain-containing 16, cell death-inducing DFFA-like effector A, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), and other brown adipocyte markers. The mice also exhibited enhanced AMPK alpha1 phosphorylation (Wang et al., 2015). Studies have revealed that resveratrol and its metabolites can permeate the blood–brain barrier. Treatment of patients with mild–moderate AD with resveratrol maintains the integrity of the blood–brain barrier and contributes to cognitive and functional improvement by reducing the expression of matrix metalloproteinase-9 and inducing adaptive immune responses (Moussa et al., 2017). Resveratrol supplements in the diet increase metabolic rate, insulin sensitivity, mitochondrial biogenesis, and physical endurance in mice; they also improve the accumulation of fat and cognitive deficits of AD (Porquet et al., 2013; Moussa et al., 2017; Orlandi et al., 2017). Moreover treatment with resveratrol prolongs the mean and maximal lifespan of SAMP8 mice, a model of age-related AD, by activating the AMPK and SIRT1 pathways (Porquet et al., 2013; Bhullar and Hubbard, 2015). Resveratrol supplements are shown to extend the lifespan of Nothobranchius guentheri (a new model organism for aging studies), enhance the cognitive and locomotor activities, and delay the activation of senescence-associated markers when compared with the control group without affecting its body size (Yu and Li, 2012). Resveratrol treatment during later years in life has been proven to extend the lifespan and age-related symptoms of many model organisms, such as yeast, Caenorhabditis elegans, and Drosophila (Lee et al., 2016; Orlandi et al., 2017; Khan M. et al., 2019). However, recent evidence has been inconsistent. A study reveals that long-term resveratrol treatment reduces the age-related oxidative damage to DNA, lipid, and protein. Still, the study also suggests that a 12-month resveratrol intake may induce renal toxicity (Wong et al., 2009). Another study mentioned that red wine intake or oral resveratrol could delay vascular aging but does not affect the lifespan of rats (da Luz et al., 2012). A clinical randomized controlled trial also indicated that resveratrol treatment does not improve glucose and lipid metabolism or the inflammatory status of middle-aged men with metabolic syndrome (Kjær et al., 2017). Therefore, further studies are required regarding the dosage and duration of resveratrol consumption. Aging is the result of many factors in the body and these findings indicate that resveratrol is a potential antiaging therapy due to its abilities to suppress oxidative stress, inhibit inflammation, and regulate mitochondrial function and apoptosis (Zhou et al., 2021).

Curcumin is a natural dietary polyphenol in Curcuma longa exhibiting various biological and pharmacological properties including antioxidant, immunomodulatory, anti-inflammatory, and antimicrobial properties (Abrahams et al., 2019; Khan H. et al., 2019). The chemical structure of curcumin is 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione. It has predominantly pro-health benefits and is regularly used as a cadioprotective, nephroprotective, hepatoprotective, antineoplastic, antirheumatic, and antiaging natural plant compound (Abrahams et al., 2019; Benameur et al., 2021). Curcuminoids have been approved by the US Food and Drug Administration (FDA) as “Generally Recognized As Safe” (GRAS), and good tolerability and safety profiles have been shown by clinical trials, even at doses between 4,000 and 8,000 mg/day and of doses up to 12,000 mg/day of 95% concentration of three curcuminoids: curcumin, bisdemethoxycurcumin, and demethoxycurcumin (Lao et al., 2006). Toxicity studies have claimed that curcumin is a safe compound even at high doses (Hewlings and Kalman, 2017). Sudeep et al. (2021) confirmed the safety of a higher dose of turmeric extract/curcumin (500 mg/d) over a longer duration (90 days) in healthy subjects and opposed the possibility of any hepatic damage caused by turmeric/curcumin supplementation. However, current research suggests some potential risks with its use. Luber et al. (2019) reported two case studies indicating liver toxicity due to the consumption of turmeric supplements. A study performed a comprehensive assessment of the effects of parenteral administration of turmeric extract (intraperitoneal) with low (100 mg/kg) and high doses (250 mg/kg) in comparison to oral curcumin (500 mg/d) administration in a streptozocin (STZ)-induced diabetic rat model, and found that low and high doses of turmeric showed protective effects histologically on the pancreas and the kidneys, high doses both injected and orally administered caused an elevation of liver enzymes and liver damage (Essa et al., 2019). According to the World Health Organization and Food and Agriculture Organization, the recommended maximum intake of curcumin is 1 mg/kg body weight (Soleimani et al., 2018). Several studies have reported that curcumin can prevent and treat several age-related diseases. Studies have also shown that curcumin can remarkably extend lifespan and promote healthy aging in mice, Caenorhabditis elegans, yeasts (Stępień et al., 2020), and Drosophila (Suckow and Suckow, 2006; Esquivel et al., 2020). The mechanisms underlying curcumin-related effects on biological aging have been proposed, including inducing autophagy, inhibiting inflammation and oxidation, stimulating AMPK and SIRT1 pathways, inhibiting the mammalian target of rapamycin (mTOR) signaling pathway, and maintaining mitochondrial function (Benameur et al., 2021).

Curcumin also strongly prevents oxidative stress and it can protect against lipid and protein oxidation. Furthermore, it can eliminate ROS, reduce the levels of malondialdehyde (MDA), protein carbonyls, thiols, and nitrotyrosines, and stimulate the activities of SOD and catalase. A meta-analysis of randomized controlled trials suggested that exposure to curcumin for ≥4 weeks significantly reduced the MDA levels in serum, glutathione peroxidase activity in erythrocytes, and increased SOD activity (Qin et al., 2018). Rahman et al. investigated the effects of curcumin on oxidative stress in a D-galactose and naturally-induced aging mouse model. Curcumin improved retention and freezing memory and ameliorated the levels of oxidative stress biomarkers (ROS and RNS) in the D-galactose and naturally-induced aging mice. The antiaging effects of curcumin may be attributed to the upregulation of antioxidant enzymes through binding with glutathione S-transferase A1, glutathione S-transferase omega-1, kelch-like ECH-associated protein 1, and inhibition of oxidative damage through binding with beta-secretase 1 and amine oxidase [flavin-containing] A (Rahman et al., 2022). Another study reported that curcumin attenuated H₂O₂-induced oxidative stress in RAW264.7 cells by increasing the activities of antioxidant enzymes (CAT, SOD, and GSH-PX) and activating the Nrf2-Keap1 signaling pathway (Meng et al., 2021). Curcumin also antagonizes oxidative stress in blood vessels, muscles, and liver by upregulating SIRT1 and Nrf2 and downregulating the p53/p21 pathway (Ren et al., 2019; Cox et al., 2022). Clinical and nutritional epidemiological studies have revealed that the long-term ingestion of curcumin can prevent cardiovascular disease and reduce pathological factors triggering cardiovascular diseases (Hong et al., 2019). The oral administration of curcumin in spontaneously hypertensive rats significantly reduced the expression of connective tissue growth factor, type III collagen, and fibronectin in the left ventricle of the heart and upregulated peroxisome proliferator-activated receptor gamma (PPARγ) activity, thereby alleviating hypertension-induced myocardial fibrosis (Meng et al., 2014). The antioxidant effects of curcumin can reduce oxygen radicals produced in vivo, induce antiapoptotic effects, and resist myocardial infarction-induced cardiac dysfunction (Lv et al., 2016). Studies reporting vascular endothelial dysfunction in porcine coronary arteries have revealed that curcumin can impede homocysteine-induced endothelium-dependent vasodilatory dysfunction, reduce endothelial-type nitric oxide synthase levels, and decrease the production of superoxide anion radicals, thereby alleviating vascular endothelial dysfunction (Ramaswami et al., 2004). Altogether, these findings suggest that as a major component of the daily diet, curcumin can prevent cardiovascular disease development. The cardioprotective effects of curcumin may lie in its ability to directly influence various enzymes (Yuan et al., 2005; Potter, 2013).

Many recent studies in vitro and in vivo have proved that curcumin has protective effects against neuroinflammation (Bielak-Zmijewska et al., 2019; Lin et al., 2019; Cianciulli et al., 2022). The anti-inflammatory effects of curcumin have contributed to multiple molecular targets including NF-κB. A study revealed that curcumin treatment after LPS stimulation significantly reduced the release of inflammatory mediators and suppressed microglial TLR4/MyD88/NF-κB signaling pathway protein expressions along with neuronal apoptosis in experimental traumatic brain injury (Zhu et al., 2014). Along with suppressing the NF-κB signaling pathway in inflammatory processes, curcumin supplementation can increase the production of anti-inflammatory cytokines in murine BV-2 microglia cells via the JAK/STAT/SOCS signaling pathway (Porro et al., 2019). Other anti-inflammatory effects of curcumin include downregulating the levels of monocyte chemoattractant protein-1, COX-2, lipoxygenase, iNOS, MAPK, and other inflammatory mediators (Cianciulli et al., 2022). As an alternative epigenetic modulator, curcumin enhances SIRT1 expression and ultimately has protective effects against many neurological disorders (Zendedel et al., 2018). Although curcumin has several pharmacological properties against many disorders, it has poor bioavailability and low gastrointestinal absorption, which are mainly attributed to poor solubility and rapid clearance (Shabbir et al., 2021). The use of curcumin-loaded nanoparticles has been elucidated to be a safe and novel therapeutic strategy (Yavarpour-Bali et al., 2019; Tagde et al., 2021). These findings indicate that curcumin intake in elderly individuals may promote healthy aging and minimize the risk of age-related diseases. However, higher doses of turmeric and curcumin as an oral supplement should be used with caution in future studies and in clinical trials since they are potentially hepatotoxic.

Lignans are dimers derived from cinnamic acid and its derivatives (Rodríguez-García et al., 2019). Lignans are molecules with two phenyl propane units coupled at the central carbon of the side chain, whereas compounds with alternative coupling are called neolignans (Lu et al., 2016). Dietary sources of lignans are particularly abundant, including oilseeds (flaxseed, sesame, linseed, and sunflower), whereas other foods contain lower levels (Sun J. et al., 2018). However, dietary surveys have revealed that whole grains (especially rye), legumes, fruits, vegetables, nuts, tea, and coffee can also be considered good sources of lignans. Lignans can be classified into eight subgroups, arylnaphthalenes, aryltetralins, dibenzocyclooctadienes, dibenzylbutanes, dibenzylbutyrolactones, dibenzylbutyrolactols, furans, and furofurans, according to the cyclization and oxygen incorporation patterns (Osmakov et al., 2022). Lignans are metabolized to enterodiol and enterolactone by gut microorganisms and exhibit various biological activities, including anti-inflammatory and antioxidative properties. Lignans can also combat the progression of age-related diseases such as cancer, cardiovascular diseases, neurodegenerative diseases, and metabolic diseases (Šmejkal et al., 2010; Sun J. et al., 2018; Egawa et al., 2020; Maia et al., 2020).

Shimoyoshi et al. reported that sesame lignans could prevent age-related cognitive decline by reducing reactive carbonyl species production in aging-accelerated mice via antioxidant properties; thus, long-term consumption of sesame lignans might effectively prevent age-related brain dysfunction (Shimoyoshi et al., 2019). Similarly, dibenzocyclooctadiene lignans isolated from a Chinese botanical drugs, Schisandra chinensis, have anti-inflammatory and antioxidant properties, as well as improve cognitive function (Hu et al., 2014). High levels of dietary lignan intake significantly reduces the risk of mortality from postmenopausal breast cancer (Franco et al., 2005) and is also associated with a lower risk of other cancer types and developing cardiovascular diseases in women experiencing postmenopausal symptoms and elderly men (Pellegrini et al., 2010; Peterson et al., 2010; Lin et al., 2014). Lignans exert anti-inflammatory and antioxidative effects by inhibiting NF-κB, c-Jun N-terminal kinase (JNK)/p38 MAPK, and PI3K/Akt signaling pathways and activating the antioxidant Nrf2/HO-1 pathway (Osmakov et al., 2022). Nectandrin B, a bioactive lignan isolated from nutmeg, reduces cellular oxidative stress by directly scavenging free radicals or indirectly inducing antioxidant enzyme expression by activating AMPK, thereby reducing cellular senescence. It significantly reduces H₂O₂- and palmitate-induced intracellular ROS production in young and elderly human diploid fibroblasts (HDFs), stimulates the expression of SOD I and II in aged HDFs, activates the PI3K/Akt pathway, reversing ERK1/2 and p38 activity (Jang et al., 2019). Lignans from guaiac resin are shown to decrease nitric oxide production in interleukin 1β-treated rat hepatocytes, exhibiting anti-inflammatory effects. Furthermore, lignans ameliorate silica-related oxidative stress, immune-related inflammatory response, and fibrosis by inhibiting TLR-4/NLRP3/TGF-β signaling and increasing mitochondrial membrane potential in vitro and in vivo. Thus, they inhibit ROS production, macrophage polarization, and myofibroblast differentiation (Liu et al., 2021). Lignans also sensitize cancer cells to treatment-induced cytotoxicity by inhibiting cell survival pathways including PI3K/Akt, NF-κB, and X-linked apoptosis inhibitory protein, and by stimulating apoptotic pathways such as tumor suppressor p53 (Saarinen et al., 2010). Current observations highlighted the bioactive properties of lignans as human health-promoting molecules. Due to their various bioactive properties, dietary intake of lignan-rich foods may prevent certain types of cancers and lower the risk of developing cardiovascular disease. Nonetheless, further human studies are warranted to evaluate lignan bioavailability resulting from different traditional dietary patterns, thus affect the rational promotion of healthy lignan-rich diets.

Bioactive polyphenols, such as quercetin, luteolin, EGCG, resveratrol, curcumin, and lignans have a substantial impact on the aging process in different organisms. Polyphenols have some advantages compared to chemical inducers of autophagy due to their intrinsic natural bio-compatibility and safety. In this context, polyphenols can be used as part of the diet or as separate compounds (supplements) that have potential therapeutic effects on healthy aging (Ullah and Khan, 2018; Yessenkyzy et al., 2020). However, the clinical efficacy and potential toxicity of high dose intake of polyphenols need to be further studied and validated in the near future.