Dietary Anti-Aging Polyphenols And Potential Mechanisms Part 2

3. Potential Anti-Aging Mechanisms 

3.1. The Antioxidant Effects of Polyphenols

According to the free radical theory, aging results from chronic imbalance (extra amount of ROS) between ROS and antioxidants, also called oxidative stress, which leads to cellular senescence, functional alterations, and pathological conditions [97,98] as discussed above. It has been well-acknowledged that many polyphenolic compounds possess antioxidant properties. As exogenous antioxidants, polyphenols can combat ROS by at least four mechanisms as highlighted below.

Glycoside of cistanche can also increase the activity of SOD in heart and liver tissues, and significantly reduce the content of lipofuscin and MDA in each tissue, effectively scavenging various reactive oxygen radicals (OH-, H₂O₂, etc.) and protecting against DNA damage caused by OH-radicals. Cistanche phenylethanoid glycosides have a strong scavenging ability of free radicals, a higher reducing ability than vitamin C, improve the activity of SOD in sperm suspension, reduce the content of MDA, and have a certain protective effect on sperm membrane function. Cistanche polysaccharides can enhance the activity of SOD and GSH-Px in erythrocytes and lung tissues of experimentally senescent mice caused by D-galactose, as well as reduce the content of MDA and collagen in lung and plasma, and increase the content of elastin, have a good scavenging effect on DPPH, prolong the time of hypoxia in senescent mice, improve the activity of SOD in serum, and delay the physiological degeneration of lung in experimentally senescent mice With cellular morphological degeneration, experiments have shown that Cistanche has the good antioxidant ability and has the potential to be a drug to prevent and treat skin aging diseases. At the same time, echinacoside in Cistanche has a significant ability to scavenge DPPH free radicals and can scavenge reactive oxygen species, prevent free radical-induced collagen degradation, and also has a good repair effect on thymine free radical anion damage.

Click on maca ginseng antioxidant cistanche

【For more info:george.deng@wecistanche.com / WhatApp:8613632399501】

First, polyphenols can directly scavenge ROS because of the presence of phenolic hydroxyl groups on their molecules. The ROS-scavenging capacity of polyphenols depends on the number and position of the hydroxyl group and substituent patterns, as well as the glycosylation of phytochemical molecules [99–101]. For example, kaempherol-3,7,4'-trimethylether,  kaempherol-3,4'-dimethylether, kaempherol-7-neohesperidoside, and kaempferol, which have 1 (in the 5-position), 2, 3, and 4 hydroxyl substitutions, respectively, are 0, 1.0, 1.6, and 2.7 times of Trolox equivalent antioxidant activity, respectively [102]. These data suggest that phenolic compounds with more hydroxyl groups may have a stronger antioxidant capacity. Moreover, substitution patterns in the B-ring and A-ring, as well as the 2, 3-double  bond (unsaturation) and the 4-oxo group in the C-ring, are important for the antioxidant capacity of the compounds [103,104]. Polyphenols with a 30,40 -o-dihydroxyl group in the B-ring, a 2,3-double bond combined with a 4-keto group in the C-ring, and a 3-hydroxyl  group had the highest antioxidant activity [103,105]. Flavanols with a galloyl moiety had higher antioxidant activity than those without, and a B-ring 30,40,50 -trihydroxy group further improved their efficacy [103,105]. When C-3’, and 4’ positions in the B ring of flavonoids are replaced by hydroxyl groups, the antioxidant activity improved remarkably, however,  the numbers and substitutional positions of methoxyl and glycosyl seemed to have little effect on the antioxidant activity [106]. In an animal study, C57BL/6J mice received a  polyphenol-rich grape skin extract (PGE) diet at a dose of 200 mg/kg body weight (BW)/d  for a 3-week, 6-month, and life span [107]. The results of this study showed that lifelong PGE feeding resulted in a transient, but significant change in the survival curve, although it did not affect the overall survival rate of the animals [107]. These effects of PGE are associated with enhanced signal pathways involved in energy homeostasis, antioxidant defense, and mitochondrial biogenesis, including SIRT stimulation [107].

Second, polyphenols can exert antioxidant activity by regulating endogenous antioxidant and oxidase enzyme production and activity. As a primary mechanism neutralizing oxidants, two intracellular enzymes, sodium oxide dismutase 1 (SOD1) in the cytosol,  and SOD2 in the matrix of mitochondria, quickly convert superoxide to hydrogen peroxide. Hydrogen peroxide is further deactivated by catalase (CAT) or glutathione peroxidases (GSH-Px) to water and oxygen. Numerous studies reported that curcumin (8 mg/kg) [108], EGCG (100 mg/kg) [109], or quercetin ( 0.027% in the diet) [110] reversed oxidative stress caused a reduction of GSH and SOD levels in mice or rats. Resveratrol protects against oxidative damage by increasing expressions of SOD1, CAT, and heme oxygenase-1 (HO- 1) as well as the activity of SOD [111,112]. Similarly, oral administration of epimedium flavonoids improved CAT and GSH-Px activities by 13.58% and 5.18%, respectively, in D. melanogaster [113]. Genistein dose-dependently increased GSH-Px in breast cancer cells [114]. Flavonoid chrysin and its derivatives exhibit a high selectivity of GSH efflux (transporting intracellular GSH out of the cell), which can be used to kill chemoresistant cancer cells [115].

Third, polyphenols may enhance cellular antioxidant activity by regulating Nrf2-  mediated pathways. Nrf2 is a transcriptional factor regulating the expression of several detoxifying enzymes, including SOD, GPx1, GSH, NADP(H) quinone oxidoreductase 1 (NQO1), GST, and HO-1, by binding to the antioxidant-response elements (AREs) in the promoter regions of the genes of these enzymes [116]. Numerous polyphenols, including EGCG [117], luteolin [118], curcumin [119], and epicatechin [120] can enhance Nrf2 DNA-binding activity or protein expression and subsequently increase NQO1, HO-1, and SOD  expression. Resveratrol (25–50 µM) increased 2.5-fold NQO1 protein levels and 3- to 5-fold NQO1 enzymatic activity in human k562 cells [121]. The possible molecular mechanism is that resveratrol disrupts the Nrf2-Keapl complex in the cytosol, which stimulates the translocation of Nrf2 to the nucleus where it locates the ARE-containing 5’-promoter region of NQO1, leading to its transcriptional activation [121].

Lastly, there is emerging evidence showing that polyphenols may counteract ROS  via regulating microRNAs (miRNA, see more details in the next section). MicroRNAs (miRNAs) are endogenous, noncoding, single-stranded, and short (19-22 of 22 nucleotides) RNAs. miRNAs sequence-specifically bind to the 30 UTR of mRNA to repress or induce translation to regulate diverse biological pathways and processes, including cell death and proliferation, and human diseases like cancer and aging. Up to now, more than 38,589 miRNAs have been cataloged in airbase (http://www.mirbase.org, accessed on 1 December 2020),  and nearly 60% of all human transcripts are predicted to be regulated by miRNAs [122]. It was recently found that some polyphenols, including quercetin, hesperidin, naringenin,  anthocyanin, catechin, and curcumin reversed ApoE mutant-induced changes of miRNAs,  including mmu-miR-291b-5p, mmu-miR-296-5p, mmu-miR-30c-1, mmu-miR-467b, and  mmu-miR-374, which collectively regulate 34 common pathways, including the pathway of GSH metabolism [123]. Another study found that curcumin downregulated the expression of miR-17-5p, miR-20A, and miR-27a, which was shown to modulate ROS production [124]. Dietary quercetin supplementation (2 mg/g diet, 6 weeks) increased the expression levels of hepatic miR-122 and miR-125b in high-fat diet-induced obese mice [125], which were associated with redox factor 1, a modulator of oxidative stress [126]. Therefore, as shown in Figure 1, polyphenols may protect cells from oxidative stress by multiple mechanisms. Indeed, it was shown that curcumin could directly scavenge ROS [127], increase the expression of endogenous antioxidants [108], activate the Nrf2 pathway [119], and modulate miRNAs [128].

3.2. Polyphenols and Cellular Senescence 

3.2.1. Cellular Senescence and Aging

Aging, happening to each living creature, is a complicated degenerative process. One of the earliest written records of human pursuits for anti-aging drugs can be found in the earliest Chinese pharmacy monograph, Shennong Materia Medica, in B. C. 220. Indeed, scientists constantly sought to decipher the driving forces behind aging and approximately 300 theories of aging have been proposed, however, there is no dominant one that has been generally accepted by the scientific community to convincingly explain the aging process [129]. Among the early theories of aging, the activity theory defines aging as the maintenance of activities and attitudes of the young and middle ages as long as possible [130]. The evolutionary theory indicates that aging is not driven by damage, but causes organelle damage and functional decline [131]. Getting old is a  developmental program, which never stops. The free radical theory proposes that aging is the result of cumulative damage to DNA, proteins, lipids, and other macromolecules caused by un-neutralized free radicals [132]. There is a dynamic balance between oxidants (ROS, and reactive nitrogen species, RNS) and antioxidants in the body. ROS,  primarily superoxide anion (O2–˙), are primarily produced by mitochondrion during energy production (about 2% of total oxygen consumption) [133]. Superoxide is quickly converted to hydrogen peroxide by two intracellular enzymes, SOD1 in the cytosol and SOD2 in the matrix of mitochondria. Hydrogen peroxide is further converted into water and oxygen by catalase or GPx [134]. Endogenous antioxidant GSH and exogenous antioxidants,  including vitamins C and E, dietary polyphenols are also important ROS scavengers. Chronic imbalance (extra amount of ROS) between ROS and antioxidants leads to cellular senescence, functional alterations, and pathological conditions [97,98].

Senescence (from the Latin word “senex“, meaning growing old), or cellular aging,  is an irreversible cell-cycle arrest in the G1 phase, elicited by excessive intracellular or extracellular stress or damage [135,136]. Senescence is necessary to restrict the replication of old and damaged cells and other detrimental alterations, thereby inactivating potential malignant transformation [135,137]. Based on the kinetics of cell senescent processes, cellular senescence can be primarily categorized as acute (transient) or chronic (persistent)  senescence. While acute senescence is part of normal biological processes necessary for maintaining physiological homeostasis and has a beneficial effect on tissues during embryonic development, wound healing, or tissue repair, chronic senescence has detrimental effects within cells and tissues, particularly in the elderly because these cells and tissues are not able to clean damaged cells through the autophagic process, and leads to aging and aging-associated diseases such as cancer [138]. Increasing evidence shows that senescent cells accumulate in tissues of humans, primates, and rodents with age [139], and the accumulation of senescent cells was also associated with aging-related diseases such as diabetes [140], atherosclerosis [141], and obesity [142]. Interestingly, it was shown that oxidative stress is one of the major inducers of cell senescence [143,144]. Therefore, it is tempting to speculate that polyphenols as exogenous antioxidants may have the potential to prevent cellular senescence and thereby the aging process.

3.2.2. The Effects of Polyphenols on Cellular Senescence

Polyphenols treatment has beneficial effects on certain types of disease due to their action on preventing cellular senescence. Combination treatment with a senolytic drug Dasatinib and quercetin, a well-studied flavonol present in many plants, reduced the accumulation of senescent cells in adipose tissue by suppressing the senescence-associated β-galactosidase activity [145]. In agreement with this in vitro finding, the combination of Dasatinib and quercetin alleviated senescence-related idiopathic lung fibrosis [146]. In a senescence mouse model SAMP8 mice, the group consuming a diet with 532 mg/kg olive oil phenols for 4.5 months showed significantly lower levels of oxidative damage in the heart and induced longevity-related genes expression as compared to the group consuming a diet with only 44 mg/kg olive oil polyphenols [39]. Consistently, it was shown that chronic treatment of pre-senescent human lung and neonatal human dermal fibroblasts with 1 µM hydroxytyrosol or 10 µM oleuropein aglycone effectively reduced senescent cell numbers as demonstrated by measuring β-galactosidase-positive cell numbers and  p16 protein expression [147]. In line with this finding, oleuropein treatment delayed the appearance of senescence morphology and extended the life span of human embryonic fibroblasts IMR90 and WI38 cells by approximately 15% [148]. Gallic acid was reported to suppress β-galactosidase activity and the expression of oxidative stress markers in rat embryonic fibroblast cells [149]. These results suggest that polyphenols may be able to modulate cellular senescence thereby influencing the aging process.

3.3. Polyphenols May Exert Anti-Aging Effects by Targeting microRNA 

MicroRNAs (miRNAs) are small non-coding RNA molecules secreted from cells into peripheral body fluids, including blood, saliva, and urine, either in association with RNA-binding proteins like Argonaute 2, or bound to high-density lipoproteins, and some ‘circulatory’ miRNAs have been proposed as noninvasive biomarkers of aging [150]. Numerous miRNAs have been shown to directly affect lifespan as demonstrated by overexpressing or knockdown of the miRNA in C. elegans, Drosophila, and mice. These miRNAs, such as  miR-125, miR-17, let-7, AGO1, and AGO2, regulated well-known aging signaling pathways,  including the target of rapamycin (TOR), insulin/insulin-like growth-factor (IGF-1) signaling,  sirtuins deacetylases, mitochondrial/ROS signaling, and DNA-damage response [151]. In addition, using cells or mouse models, several miRNAs, including miR-1000,  miR-455-3p, miRNA-17/20a, and miR-34a, have been shown to extend longevity by improving aging-caused dysfunctions of organs such as the brain [152], muscle [153],  bone [154], and heart [155], respectively. However, most studies exploring and identifying lifespan-modulating miRNAs used C. elegans and Drosophila, and miR-17 is the only miRNA that has been reported to directly extend lifespan in mice [156].

While studies investigating the effects of polyphenols on miRNA expression are limited, which is an intriguing area to explore in the future, emerging evidence shows that dietary intake of some polyphenols modulates the expression of miRNAs that are involved in longevity. One study found that a low dose of supplementation of quercetin,  hesperidin, naringenin, anthocyanin, catechin, or curcumin (0.006%, w/w, two weeks) in the diet modulated the expression of a broad range of miRNAs and rectified the ApoEmutantation-induced changes of miRNAs in the livers of ApoE-deficient mice [123]. These polyphenol-modulated miRNAs, including mmu-miR-291b-5p, mmu-miR-296-5p, mmumiR-30c-1, mmu-miR-467b, and mmu-miR-374, regulate 30 common pathways, including MAPK signaling pathway, the calcium signaling pathway, the insulin signaling pathway, as well as oxidative phosphorylation, some of which are involved in longevity in mice [123]. In addition, miR-17, a mammalian longevity miRNA that directly targets insulin receptor substrate (Irs1) and adenylates cyclase 5 (Adcy5), can be regulated by polyphenols. For instance, catechin, proanthocyanins, naringin [123], and genistein [157] upregulated miR- 17 expression in mice. Similarly, the expression of let-7, a common longevity miRNA conserved across C. elegans, Drosophila, mouse, and humans, was enhanced by catechin,  proanthocyanins, and naringin in ApoE mice [123]. Therefore, some polyphenols may act through miRNAs to regulate aging-related pathways, suppress inflammation and ROS production, and improve lipid metabolism, leading to a healthier and extended lifespan [128]. The effect of polyphenols on the expression of miRNAs may not be specific. For instance, epicatechin was shown to modulate more than 73 miRNAs involved in various cellular functions in human endothelial cells [158]. In diabetic patients, dietary intake of grape extract (8.1-16.2 mg polyphenols) upregulated miR-21, miR-181b, miR-663, and miR-30c committed with the lower levels of inflammatory cytokines such as IL-6,  chemokine ligand 3, IL-1, and TNF-α [159]. However, it is unclear whether any of these miRNAs directly mediates the anti-inflammatory action of the grape extract.

3.4. Polyphenols and NO Bioavailability 

Endothelial dysfunction, resulting from inflammation, obesity, diabetes, hypertension,  hyperlipidemia, and other related metabolic syndromes, is a major pathogenic cause of cardiovascular disease [160]. Endothelial dysfunction impairs the production and bioavailability of endothelial nitric oxide (NO) synthase (eNOS)-derived NO, which is the key regulator of vascular tone, blood pressure, and vascular inflammation [161]. The endothelial production and bioavailability of NO also progressively decrease with aging [162],  which is at least partially ascribed to the increased production of ROS [163,164]. In normal conditions, eNOS is coupled to generate NO from the oxidation of L-arginine. However, excess oxidative stress causes the oxidation of tetrahydrobiopterin, a critical cofactor for eNOS,  which leads to eNOS uncoupling from producing NO, but a diversion to reduce oxygen to form superoxide [165,166], thereby reducing the bioavailability of NO that subsequently accelerates the development of vascular disease [163,164]. Thus, promoting the eNOS expression/activity and/or NO bioavailability would be effective methods to alleviate aging-associated endothelial dysfunction and subsequently delay the development of cardiovascular disease. Plenty of studies have demonstrated that polyphenolic compounds have protective actions over cardiometabolic syndrome [167], among which eNOS expression/activity and NO bioavailability are the most determined mechanisms [161,168–170]. Morin, a flavonoid, can effectively protect human ventricular myocytes, saphenous vein endothelial cells, and erythrocytes against oxyradicals-induced damage [171]. Further,  morin treatment promoted eNOS-mediated NO production and vasodilation of the aorta in STZ-induced diabetic mice by activating the Akt signaling pathway [172,173]. As aforementioned, resveratrol has attracted mounting research interests [174,175]. Resveratrol treatment increased the eNOS transcriptional activity and the eNOS-derived NO production in human umbilical vein endothelial cells [176]. Protocatechuic acid (PCA) is a major metabolite of green tea polyphenols with a strong antioxidant property [177]. Administration of PCA (200 mg/kg/day) significantly improved insulin- and IGF-1-induced  vasorelaxation in aging spontaneously hypertensive rats via activating the PI3K/NOS/NO  pathway [178]. Cyanidin-3-glucoside (Cy3G), a typical anthocyanin found in deep-colored plants [179], has been shown to promote eNOS protein expression and subsequently increase NO output in bovine artery endothelial cells [170]. Interestingly, multiple polyphenols, including catechin, oleuropein, quercetin, and EGCG, were found to reduce nitrite to NO in the stomach, suggesting that polyphenols may be a nitrite reductant due to the hydroxyl groups on the phenol ring [180]. Furthermore, 12 weeks of curcumin supplementation improved resistance artery endothelial function by increasing vascular NO  bioavailability and reducing oxidative stress [181]. In diabetic rats, treatment with green tea extract, which is primarily composed of EGCG, ameliorated the diabetes-induced reduction of tetrahydrobiopterin, uncoupling of eNOS, and thus increased NO bioavailability and reduced oxidative stress [165].

3.5. Polyphenols May Promote Mitochondrial Function

In addition to the direct action on eNOS expression/activity, polyphenols were reported to activate Sirt1 [182,183], which is an upstream regulator of eNOS [184,185], therefore Sirt1-mediated mitochondrial biogenesis might underlie the anti-aging actions of polyphenols against oxidative stress. Indeed, resveratrol treatment increased mitochondrial biogenesis in wild-type mice but not eNOS knockout mice [179]. Activation of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), the key regulator in mitochondrial biogenesis, has been reported to protect against aging-related diseases [16,185]. In vivo, resveratrol promoted liver PGC-1α activity and significantly extended the lifespan of mice fed a high-calorie diet [186]. In vitro, resveratrol treatment increased adenosine monophosphate (AMP)-activated protein kinase (AMPK) phosphorylation in CHO  cells [186], suggesting the involvement of AMPK/Sirt1 signaling pathway in the action of resveratrol extending lifespan in mammals. Polyphenols treatment (resveratrol, apigenin, and S17834, a synthetic polyphenol) have been reported to phosphorylate AMPK in HepG2 cells, thereby subsequently protecting hepatocytes from high glucose-induced lipid accumulation [187]. Dysfunctional mitochondria can cause imbalanced ROS accumulation based on the free radical theory, which may exacerbate the progress of aging. Thus, targeting mitochondrial function can be an effective approach to slow aging. Interestingly,  resveratrol treatment can improve the quality of oocytes from aged cows (>10 years old) by upregulating mitochondrial biogenesis [188], suggesting a potential mechanism to slow maternal aging. Hydroxytyrosol, a phenolic compound found in olive oil, effectively increased mitochondria number in 7PA2 cells, a well-established cell model to study AD [189],  suggesting polyphenols may help alleviate the energetic deficit of AD patients.

4. Conclusions and Perspectives

Interest in the use of complementary and alternative medicine, particularly polyphenol-rich natural products, has increased considerably to improve the health and well-being of humans for the past two decades. Some polyphenols have even been shown to extend lifespan in various model organisms. Polyphenols at supraphysiological or higher doses are well recognized to directly scavenge ROS by donating an electron or hydrogen atom. However, they may exert antioxidant activity in vivo via other mechanisms as discussed in this paper, given their relatively poor bioavailability. Aging and aging-related disorders are complex and certainly influenced by dietary habits and genetic backgrounds. This review is rather narrow considering the tremendous efforts of researchers investigating the molecular mechanisms underlying the beneficial actions of polyphenols, however, we highlighted emerging evidence that may provide new mechanisms underlying the antioxidant and anti-aging actions of polyphenols. While the use of polyphenols in preventing aging-related disorders has proven to be promising in various model organism-based studies, the safety and potential health benefits from long-term use of the individual pure compound in humans are still uncertain. It should be noted that one food may contain at least several and even hundreds of polyphenols [190], and some diets such as the Mediterranean diet have multiple polyphenol-rich foods, which collectively contain 290 different polyphenols [191,192]. Therefore, it could be misleading to attribute the benefits of consuming particular polyphenol-containing foods to the individual polyphenols, which are often given at much higher doses, particularly in animal and in vitro studies, than those possibly obtained from consuming the relevant foods or supplements by humans [193]. In the future, it may be more relevant and interesting to investigate the beneficial effects of the combination of multiple polyphenols or polyphenol-rich foods, as a combination of polyphenols may exert synergistic or additive beneficial effects [192,194].

Funding: This research received no external funding. 

Conflicts of Interest: The authors declare no conflict of interest.

References

1. Willett, W.C. Diet, and health: What should we eat? Science 1994, 264, 532–537. [CrossRef] 

2. Cherniack, E.P. The potential influence of plant polyphenols on the aging process. Forsch Komplementmed 2010, 17, 181–187. [CrossRef] 

3. Barha, C.K.; Hsu, C.L.; Ten Brinke, L.; Liu-Ambrose, T. Biological Sex: A Potential Moderator of Physical Activity Efficacy on Brain Health. Front. Aging Neurosci. 2019, 11, 329. [CrossRef] 

4. Gladyshev, V.N. The Free Radical Theory of Aging Is Dead. Long Live the Damage Theory! Antioxid. Redox Sign. 2014, 20, 727–731. [CrossRef] [PubMed] 

5. Frisard, M.; Ravussin, E. Energy metabolism, and oxidative stress: Impact on the metabolic syndrome and the aging process. Endocrine 2006, 29, 27–32. [CrossRef] 

6. Bertram, C.; Hass, R. Cellular responses to reactive oxygen species-induced DNA damage and aging. Biol. Chem. 2008, 389, 211–220. [CrossRef] [PubMed] 

7. McHugh, D.; Gil, J. Senescence and aging: Causes, consequences, and therapeutic avenues. J. Cell Biol. 2018, 217, 65–77. [CrossRef] [PubMed] 

8. Rolt, A.; Cox, L.S. Structural basis of the anti-aging effects of polyphenolics: Mitigation of oxidative stress. BMC Chem. 2020, 14, 50. [CrossRef] [PubMed] 

9. Liguori, I.; Russo, G.; Curcio, F.; Bulli, G.; Aran, L.; Della-Morte, D.; Gargiulo, G.; Testa, G.; Cacciatore, F.; Bonaduce, D.; et al. Oxidative stress, aging, and diseases. Clin. Interv. Aging 2018, 13, 757–772. [CrossRef]

10. Majidinia, M.; Karimian, A.; Alemi, F.; Yousefi, B.; Safa, A. Targeting miRNAs by polyphenols: Novel therapeutic strategy for aging. Biochem. Pharmacol. 2020, 173, 113688. [CrossRef] [PubMed] 

11. Scalbert, A.; Johnson, I.T.; Saltmarsh, M. Polyphenols: Antioxidants and beyond. Am. J. Clin. Nutr. 2005, 81, 215S–217S. [CrossRef] 

12. Sandoval, V.; Sanz-Lamora, H.; Arias, G.; Marrero, P.F.; Haro, D.; Relat, J. Metabolic Impact of Flavonoids Consumption in Obesity: From Central to Peripheral. Nutrients 2020, 12, 2393. [CrossRef] 

13. Ebrahimpour, S.; Zakeri, M.; Esmaeili, A. Crosstalk between obesity, diabetes, and Alzheimer’s disease: Introducing quercetin as an effective triple herbal medicine. Ageing Res. Rev. 2020, 62, 101095. [CrossRef] 

14. Singh, A.; Yau, Y.F.; Leung, K.S.; El-Nezami, H.; Lee, J.C. Interaction of Polyphenols as Antioxidant and Anti-Inflammatory Compounds in Brain-Liver-Gut Axis. Antioxidants 2020, 9, 669. [CrossRef] [PubMed] 

15. Si, H.; Liu, D. Dietary antiaging phytochemicals and mechanisms associated with prolonged survival. J. Nutr. Biochem. 2014, 25, 581–591. [CrossRef] 

16. Baur, J.A.; Pearson, K.J.; Price, N.L.; Jamieson, H.A.; Lerin, C.; Kalra, A.; Prabhu, V.V.; Allard, J.S.; Lopez-Lluch, G.; Lewis, K.; et al. Resveratrol improves the health and survival of mice on a high-calorie diet. Nature 2006, 444, 337–342. [CrossRef] 

17. Pearson, K.J.; Baur, J.A.; Lewis, K.N.; Peshkin, L.; Price, N.L.; Labinskyy, N.; Swindell, W.R.; Kamara, D.; Minor, R.K.; Perez, E.;  et al. Resveratrol delays age-related deterioration and mimic transcriptional aspects of dietary restriction without extending life span. Cell Metab. 2008, 8, 157–168. [CrossRef] [PubMed] 

18. Miller, R.A.; Harrison, D.E.; Astle, C.M.; Baur, J.A.; Boyd, A.R.; de Cabo, R.; Fernandez, E.; Flurkey, K.; Javors, M.A.; Nelson, J.F.;  et al. Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice. J. Gerontol. Ser. A Biol. Sci. Med Sci. 2011, 66, 191–201. [CrossRef] [PubMed] 

19. Strong, R.; Miller, R.A.; Astle, C.M.; Baur, J.A.; de Cabo, R.; Fernandez, E.; Guo, W.; Javors, M.; Kirkland, J.L.; Nelson, J.F.; et al. Evaluation of Resveratrol, Green Tea Extract, Curcumin, Oxaloacetic Acid, and Medium-Chain Triglyceride Oil on Life Span of Genetically Heterogeneous Mice. J. Gerontol. Ser. 2012, 68, 6–16. [CrossRef] 

20. Reutzel, M.; Grewal, R.; Silaidos, C.; Zotzel, J.; Marx, S.; Tretzel, J.; Eckert, G.P. Effects of long-term treatment with a blend of highly purified olive secoiridoids on cognition and brain ATP levels in aged NMRI mice. Oxidative Med. Cell. Longev. 2018, 2018. [CrossRef] [PubMed] 

21. Si, H.; Fu, Z.; Babu, P.V.; Zhen, W.; Leroith, T.; Meaney, M.P.; Voelker, K.A.; Jia, Z.; Grange, R.W.; Liu, D. Dietary epicatechin promotes survival of obese diabetic mice and Drosophila melanogaster. J. Nutr. 2011, 141, 1095–1100. [CrossRef] 

22. Si, H.; Wang, X.; Zhang, L.; Parnell, L.D.; Admed, B.; LeRoith, T.; Ansah, T.A.; Zhang, L.; Li, J.; Ordovas, J.M.; et al. Dietary epicatechin improves survival and delays skeletal muscle degeneration in aged mice. FASEB J. 2019, 33, 965–977. [CrossRef] 

23. Donovan, J.L.; Manach, C.; Rios, L.; Morand, C.; Scalbert, A.; Rémésy, C. Procyanidins are not bioavailable in rats fed a single meal containing a grapeseed extract or the procyanidin dimer B3. Br. J. Nutr. 2002, 87, 299–306. [CrossRef] [PubMed] 

24. Koga, T.; Moro, K.; Nakamori, K.; Yamakoshi, J.; Hosoyama, H.; Kataoka, S.; Ariga, T. Increase of the antioxidative potential of rat plasma by oral administration of a proanthocyanidin-rich extract from grape seeds. J. Agric. Food Chem. 1999, 47, 1892–1897. [CrossRef] 

25. Rios, L.Y.; Bennett, R.N.; Lazarus, S.A.; Remesy, C.; Scalbert, A.; Williamson, G. Cocoa procyanidins are stable during gastric transit in humans. Am. J. Clin. Nutr. 2002, 76, 1106–1110. [CrossRef] [PubMed] 

26. Bhagwat, S.; Haytowitz, D.B.; Holden, J.M. USDA Database for the Flavonoid Content of Selected Foods, Release 3.1.; Agricultural Research Service, U.S. Department of Agriculture, Ed.; Agricultural Research Service, U.S. Department of Agriculture: Beltsville, MD, USA, 2014. 

【For more info:george.deng@wecistanche.com / WhatApp:8613632399501】