Skip to main content

Targeting Wnt signaling pathway by polyphenols: implication for aging and age-related diseases

Abstract

Age is an important risk factor for different diseases. The same mechanisms that promote aging are involved in the development and progression of age-associated diseases. Polyphenols are organic compounds found in fruits and vegetables. Due to their beneficial properties (e.g. antioxidant and anti-inflammatory), polyphenols have been extensively used for treating chronic diseases. To exert their functions, polyphenols target various molecular mechanisms and signaling pathways, such as mTOR, NF-κB, and Wnt/β-catenin. Wnt signaling is a critical pathway for developmental processes. Besides, dysregulation of this signaling pathway has been observed in various diseases. Several investigations have been conducted on Wnt inhibitors at pre-clinical stages, showing promising results. Herein, we review the studies dealing with the role of polyphenols in targeting the Wnt signaling pathways in aging processes and age-associated diseases, including cancer, diabetes, Alzheimer’s disease, osteoporosis, and Parkinson’s disease.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

Abbreviations

PCP:

Planar cell polarity

GSK3β:

Glycogen synthase kinase 3β

CK1α:

Casein kinase 1α

APC:

Adenomatous polyposis coli

TRCP:

ββ-transducin repeat-containing protein

Lrp:

Low density lipoprotein receptor-related protein

Dvl:

Dishevelled

TCF:

T-cell factor

WRE:

Wnt response element

CBP:

Cyclic AMP response element-binding protein

SFRP5:

Secreted frizzled-related protein 5

NEAT1:

Nuclear enriched abundant transcript 1

lncRNA:

Long non-coding RNA

MALAT1:

Metastasis associated lung adenocarcinoma transcript 1

EGCG:

Epigallocatechin-3-gallate

PSC:

Pancreatic stem cell

TCF7L2:

Transcription factor 7-like 2 locus

References

  1. Aberle H, Bauer A, Stappert J, Kispert A, Kemler R (1997) beta-catenin is a target for the ubiquitin-proteasome pathway. Embo j 16(13):3797–3804

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. Ajami M, Pazoki-Toroudi H, Amani H, Nabavi SF, Braidy N, Vacca RA, Atanasov AG, Mocan A, Nabavi SM (2017) “Therapeutic role of sirtuins in neurodegenerative disease and their modulation by polyphenols”. Neurosci Biobehav Rev 73:39–47

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. Alappat L, Awad AB (2010) “Curcumin and obesity: evidence and mechanisms”. Nutr Rev 68(12):729–738

    PubMed  Article  PubMed Central  Google Scholar 

  4. Amit S, Hatzubai A, Birman Y, Andersen JS, Ben-Shushan E, Mann M, Ben-Neriah Y, Alkalay I (2002) “Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway”. Genes Dev 16(9):1066–1076

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Armas LA, Recker RR (2012) Pathophysiology of osteoporosis: new mechanistic insights. Endocrinol Metab Clin North Am 41(3):475–486

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. Becker W (2011) “Recent insights into the function of DYRK1A.” Febs J 278(2):222

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. Behrens J, Jerchow BA, Würtele M, Grimm J, Asbrand C, Wirtz R, Kühl M, Wedlich D, Birchmeier W (1998) “Functional interaction of an axin homolog, conductin, with beta-catenin, APC, and GSK3beta”. Science 280(5363):596–599

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. Ben Mansour R, Wided MK, Cluzet S, Krisa S, Richard T, Ksouri R (2017) “LC-MS identification and preparative HPLC isolation of Frankenia pulverulenta phenolics with antioxidant and neuroprotective capacities in PC12 cell line”. Pharm Biol 55(1):880–887

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Bhat A, Mahalakshmi AM, Ray B, Tuladhar S, Hediyal TA, Manthiannem E, Padamati J, Chandra R, Chidambaram SB, Sakharkar MK (2019) “Benefits of curcumin in brain disorders” Biofactors 45(5):666–689

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Borges CM, Papadimitriou A, Duarte DA, Lopes de Faria JM, Lopes JB, de Faria (2016) The use of green tea polyphenols for treating residual albuminuria in diabetic nephropathy: A double-blind randomised clinical trial. Sci Rep 6:28282

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Boyina HK, Geethakhrishnan SL, Panuganti S, Gangarapu K, Devarakonda KP, Bakshi V, Guggilla SR (2020) In silico and in vivo studies on quercetin as potential anti-Parkinson agent. Adv Exp Med Biol 1195:1–11

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. Calabrese EJ, Dhawan G, Kapoor R, Iavicoli I, Calabrese V (2016) “HORMESIS: A Fundamental Concept with Widespread Biological and Biomedical Applications. " Gerontology 62(5):530–535

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. Calabrese EJ, Mattson MP (2017) “How does hormesis impact biology, toxicology, and medicine?“ npj. Aging Mechanisms of Disease 3(1):13

    PubMed  PubMed Central  Article  Google Scholar 

  14. Cao H, Chu Y, Lv X, Qiu P, Liu C, Zhang H, Li D, Peng S, Dou Z, Hua J (2012) “GSK3 inhibitor-BIO regulates proliferation of immortalized pancreatic mesenchymal stem cells (iPMSCs)”. PLoS One 7(2):e31502

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Cascella M, Bimonte S, Muzio MR, Schiavone V, Cuomo A (2017) “The efficacy of Epigallocatechin-3-gallate (green tea) in the treatment of Alzheimer’s disease: an overview of pre-clinical studies and translational perspectives in clinical practice”. Infect Agent Cancer 12:36

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  16. Chacón MA, Varela-Nallar L, Inestrosa NC (2008) Frizzled-1 is involved in the neuroprotective effect of Wnt3a against Abeta oligomers. J Cell Physiol 217(1):215–227

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  17. Chainoglou E, Hadjipavlou-Litina D (2020) Curcumin in health and diseases: Alzheimer’s disease and curcumin analogues, derivatives, and hybrids. Int J Mol Sci 21(6):1975

  18. Chen HH, Chang PC, Chen C, Chan MH (2018) Protective and therapeutic activity of honokiol in reversing motor deficits and neuronal degeneration in the mouse model of Parkinson’s disease. Pharmacol Rep 70(4):668–676

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. Chen HH, Chang PC, Wey SP, Chen PM, Chen C, Chan MH (2018) Therapeutic effects of honokiol on motor impairment in hemiparkinsonian mice are associated with reversing neurodegeneration and targeting PPARγ regulation. Biomed Pharmacother 108:254–262

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. Chen J, Long Z, Li Y, Luo M, Luo S, He G (2019) Alteration of the Wnt/GSK3β/β–catenin signalling pathway by rapamycin ameliorates pathology in an Alzheimer’s disease model. Int J Mol Med 44(1):313–323

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chen Z, Xue J, Shen T, Mu S, Fu Q (2016) Curcumin alleviates glucocorticoid-induced osteoporosis through the regulation of the Wnt signaling pathway. Int J Mol Med 37(2):329–338

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  22. Cheng YC, Sheen JM, Hu WL, Hung YC (2017) “Polyphenols and Oxidative Stress in Atherosclerosis-Related Ischemic Heart Disease and Stroke”. Oxid Med Cell Longev 2017:8526438

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. Childs BG, Gluscevic M, Baker DJ, Laberge RM, Marquess D, Dananberg J, van Deursen JM (2017) Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov 16(10):718–735

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Chirumbolo S (2011) “Hormesis, resveratrol and plant-derived polyphenols: some comments”. Hum Exp Toxicol 30(12):2027–2030

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. Concetta Scuto M, Mancuso C, Tomasello B, Laura Ontario M, Cavallaro A, Frasca F, Maiolino L, Trovato Salinaro A, Calabrese EJ, Calabrese V (2019) Curcumin, hormesis and the nervous system. Nutrients 11(10):2417

    PubMed Central  Article  CAS  Google Scholar 

  26. Cordero JG, García-Escudero R, Avila J, Gargini R, García-Escudero V (2018) Benefit of oleuropein aglycone for Alzheimer’s disease by promoting autophagy. Oxid Med Cell Longev 2018:5010741

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  27. D’Archivio M, Filesi C, Di Benedetto R, Gargiulo R, Giovannini C, Masella R (2007) Polyphenols, dietary sources and bioavailability. Ann Ist Super Sanita 43(4):348–361

    PubMed  PubMed Central  Google Scholar 

  28. Danesi F, Kroon PA, Saha S, de Biase D, D’Antuono LF, Bordoni A (2014) Mixed pro- and anti-oxidative effects of pomegranate polyphenols in cultured cells. Int J Mol Sci 15(11):19458–19471

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Dou H, Shen R, Tao J, Huang L, Shi H, Chen H, Wang Y, Wang T (2017) Curcumin suppresses the colon cancer proliferation by inhibiting Wnt/β-catenin pathways via miR-130a. Front Pharmacol 8:877

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. Duchartre Y, Kim YM, Kahn M (2016) The Wnt signaling pathway in cancer. Crit Rev Oncol Hematol 99:141–149

    PubMed  Article  PubMed Central  Google Scholar 

  31. Dugger BN, Dickson DW (2017) Pathology of neurodegenerative diseases. Cold Spring Harb Perspect Biol 9(7):a28035

  32. Duluc L, Jacques C, Soleti R, Andriantsitohaina R, Simard G (2014) Delphinidin inhibits VEGF induced-mitochondrial biogenesis and Akt activation in endothelial cells. Int J Biochem Cell Biol 53:9–14

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. Ganesan K, Xu B (2017) A critical review on polyphenols and health benefits of black soybeans. Nutrients 9(5):455

    PubMed Central  Article  CAS  Google Scholar 

  34. García-Velázquez L, Arias C (2017) The emerging role of Wnt signaling dysregulation in the understanding and modification of age-associated diseases. Ageing Res Rev 37:135–145

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  35. Geng W, Guo X, Zhang L, Ma Y, Wang L, Liu Z, Ji H, Xiong Y (2018) Resveratrol inhibits proliferation, migration and invasion of multiple myeloma cells via NEAT1-mediated Wnt/β-catenin signaling pathway. Biomed Pharmacother 107:484–494

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. González-Sarrías A, Núñez-Sánchez M, Tomás-Barberán FA, Espín JC (2017) Neuroprotective effects of bioavailable polyphenol-derived metabolites against oxidative stress-induced cytotoxicity in human neuroblastoma SH-SY5Y cells. J Agric Food Chem 65(4):752–758

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  37. Granno S, Nixon-Abell J, Berwick DC, Tosh J, Heaton G, Almudimeegh S, Nagda Z, Rain JC, Zanda M, Plagnol V, Tybulewicz VLJ, Cleverley K, Wiseman FK, Fisher EMC, Harvey K (2019) Downregulated Wnt/β-catenin signalling in the Down syndrome hippocampus. Sci Rep 9(1):7322

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38(3):320–323

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. Guasch-Ferré M, Merino J, Sun Q, Fitó M, Salas-Salvadó J (2017) Dietary polyphenols, Mediterranean diet, prediabetes, and type 2 diabetes: a narrative review of the evidence. Oxid Med Cell Longev 2017:6723931

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. Guo J, Cai H, Zheng J, Liu X, Liu Y, Ma J, Que Z, Gong W, Gao Y, Tao W, Xue Y (2017) Long non-coding RNA NEAT1 regulates permeability of the blood-tumor barrier via miR-181d-5p-mediated expression changes in ZO-1, occludin, and claudin-5. Biochim Biophys Acta Mol Basis Dis 1863(9):2240–2254

    CAS  PubMed  Article  Google Scholar 

  41. Guttuso T Jr (2019) High lithium levels in tobacco may account for reduced incidences of both Parkinson’s disease and melanoma in smokers through enhanced β-catenin-mediated activity. Med Hypotheses 131:109302

    CAS  PubMed  Article  Google Scholar 

  42. Harb J, Lin PJ, Hao J (2019) Recent development of Wnt signaling pathway inhibitors for cancer therapeutics. Curr Oncol Rep 21(2):12

    PubMed  Article  Google Scholar 

  43. Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11(3):298–300

    CAS  PubMed  Article  Google Scholar 

  44. Hart M, Concordet JP, Lassot I, Albert I, del los Santos R, Durand H, Perret C, Rubinfeld B, Margottin F, Benarous R, Polakis P (1999) The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell. Curr Biol 9(4):207–210

    CAS  PubMed  Article  Google Scholar 

  45. Hong JY, Park JI, Lee M, Muñoz WA, Miller RK, Ji H, Gu D, Ezan J, Sokol SY, McCrea PD (2012) Down’s-syndrome-related kinase Dyrk1A modulates the p120-catenin-Kaiso trajectory of the Wnt signaling pathway. J Cell Sci 125(Pt 3):561–569

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Huang P, Yan R, Zhang X, Wang L, Ke X, Qu Y (2019) Activating Wnt/β-catenin signaling pathway for disease therapy: Challenges and opportunities. Pharmacol Ther 196:79–90

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. Ji Q, Liu X, Fu X, Zhang L, Sui H, Zhou L, Sun J, Cai J, Qin J, Ren J, Li Q (2013) Resveratrol inhibits invasion and metastasis of colorectal cancer cells via MALAT1 mediated Wnt/β-catenin signal pathway. PLoS ONE 8(11):e78700

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Jiang Q, Lei YH, Krishnadath DC, Zhu BY, Zhou XW (2021) Curcumin regulates EZH2/Wnt/β-Catenin pathway in the mandible and femur of ovariectomized osteoporosis rats. Kaohsiung J Med Sci 9(5):455

    Google Scholar 

  49. Kahn M (2014) Can we safely target the WNT pathway? Nat Rev Drug Discov 13(7):513–532

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. Keupp K, Beleggia F, Kayserili H, Barnes AM, Steiner M, Semler O, Fischer B, Yigit G, Janda CY, Becker J, Breer S, Altunoglu U, Grünhagen J, Krawitz P, Hecht J, Schinke T, Makareeva E, Lausch E, Cankaya T, Caparrós-Martín JA, Lapunzina P, Temtamy S, Aglan M, Zabel B, Eysel P, Koerber F, Leikin S, Garcia KC, Netzer C, Schönau E, Ruiz-Perez VL, Mundlos S, Amling M, Kornak U, Marini J, Wollnik B (2013) Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet 92(4):565–574

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Khan H, Ullah H, Aschner M, Cheang WS, Akkol EK (2019) Neuroprotective effects of quercetin in Alzheimer’s disease. Biomolecules 10(1):59

    PubMed Central  Article  CAS  PubMed  Google Scholar 

  52. Kimelman D, Xu W (2006) Beta-catenin destruction complex: insights and questions from a structural perspective. Oncogene 25(57):7482–7491

    CAS  PubMed  Article  Google Scholar 

  53. Kubben N, Misteli T (2017) Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases. Nat Rev Mol Cell Biol 18(10):595–609

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Kwon KR, Alam MB, Park JH, Kim TH, Lee SH (2019) Attenuation of UVB-induced photo-aging by polyphenolic-rich spatholobus suberectus stem extract via modulation of MAPK/AP-1/MMPs signaling in human keratinocytes. Nutrients 11(6):13

    Article  CAS  Google Scholar 

  55. L’Episcopo F, Serapide MF, Tirolo C, Testa N, Caniglia S, Morale MC, Pluchino S, Marchetti B (2011) A Wnt1 regulated Frizzled-1/β-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection. Mol Neurodegener 6:49

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  56. Laine CM, Joeng KS, Campeau PM, Kiviranta R, Tarkkonen K, Grover M, Lu JT, Pekkinen M, Wessman M, Heino TJ, Nieminen-Pihala V, Aronen M, Laine T, Kröger H, Cole WG, Lehesjoki AE, Nevarez L, Krakow D, Curry CJ, Cohn DH, Gibbs RA, Lee BH, Mäkitie O (2013) WNT1 mutations in early-onset osteoporosis and osteogenesis imperfecta. N Engl J Med 368(19):1809–1816

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Le Sage F, Meilhac O, Gonthier MP (2017) Anti-inflammatory and antioxidant effects of polyphenols extracted from Antirhea borbonica medicinal plant on adipocytes exposed to Porphyromonas gingivalis and Escherichia coli lipopolysaccharides. Pharmacol Res 119:303–312

    PubMed  Article  CAS  Google Scholar 

  58. Leroy K, Duyckaerts C, Bovekamp L, Müller O, Anderton BH, Brion JP (2001) Increase of adenomatous polyposis coli immunoreactivity is a marker of reactive astrocytes in Alzheimer’s disease and in other pathological conditions. Acta Neuropathol 102(1):1–10

    CAS  PubMed  Article  Google Scholar 

  59. Lewandowska U, Szewczyk K, Owczarek K, Hrabec Z, Podsędek A, Sosnowska D, Hrabec E (2013) Procyanidins from evening primrose (Oenothera paradoxa) defatted seeds inhibit invasiveness of breast cancer cells and modulate the expression of selected genes involved in angiogenesis, metastasis, and apoptosis. Nutr Cancer 65(8):1219–1231

    CAS  PubMed  Article  Google Scholar 

  60. Li X, Wang X, Xie C, Zhu J, Meng Y, Chen Y, Li Y, Jiang Y, Yang X, Wang S, Chen J, Zhang Q, Geng S, Wu J, Zhong C, Zhao Y (2018) Breast cancer stem cells. Anticancer Drugs 29(3):208–215

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. Liang Y, Zhu B, Li S, Zhai Y, Yang Y, Bai Z, Zeng Y, Li D (2020) Curcumin protects bone biomechanical properties and microarchitecture in type 2 diabetic rats with osteoporosis via the TGFβ/Smad2/3 pathway. Exp Ther Med 20(3):2200–2208

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X (2002) Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108(6):837–847

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. Lu W, Lin C, Li Y (2014) Rottlerin induces Wnt co-receptor LRP6 degradation and suppresses both Wnt/β-catenin and mTORC1 signaling in prostate and breast cancer cells. Cell Signal 26(6):1303–1309

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Luo K, Ma C, Xing S, An Y, Feng J, Dang H, Huang W, Qiao L, Cheng J, Xie L (2020) White tea and its active polyphenols lower cholesterol through reduction of very-low-density lipoprotein production and induction of LDLR expression. Biomed Pharmacother 127:110146

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 17(1):9–26

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. Maher P (2017) Protective effects of fisetin and other berry flavonoids in Parkinson’s disease. Food Funct 8(9):3033–3042

    CAS  PubMed  Article  Google Scholar 

  67. Mäkitie RE, Haanpää M, Valta H, Pekkinen M, Laine CM, Lehesjoki AE, Schalin-Jäntti C, Mäkitie O (2016) Skeletal characteristics of WNT1 osteoporosis in children and young adults. J Bone Miner Res 31(9):1734–1742

    PubMed  Article  CAS  Google Scholar 

  68. Mäkitie RE, Niinimäki T, Nieminen MT, Schalin-Jäntti C, Niinimäki J, Mäkitie O (2017) Impaired WNT signaling and the spine-Heterozygous WNT1 mutation causes severe age-related spinal pathology. Bone 101:3–9

    PubMed  Article  CAS  Google Scholar 

  69. Mileo AM, Nisticò P, Miccadei S (2019) Polyphenols: immunomodulatory and therapeutic implication in colorectal cancer. Front Immunol 10:729

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Mursaleen L, Somavarapu S, Zariwala MG (2020) Deferoxamine and curcumin loaded nanocarriers protect against rotenone-induced neurotoxicity. J Parkinsons Dis 10(1):99–111

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. Nagulapalli Venkata KC, Swaroop A, Bagchi D, Bishayee A (2017) A small plant with big benefits: Fenugreek (Trigonella foenum-graecum Linn.) for disease prevention and health promotion. Mol Nutr Food Res 61(6):1600950

    Article  CAS  Google Scholar 

  72. Nie X, Xia F, Liu Y, Zhou Y, Ye W, Hean P, Meng J, Liu H, Liu L, Wen J, Ren X, Chen WD, Wang YD (2019) Downregulation of Wnt3 suppresses colorectal cancer development through inhibiting cell proliferation and migration. Front Pharmacol 10:1110

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. Nusse R (2012) Wnt signaling. Cold Spring Harb Perspect Biol 4(5):a011163

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. Nusse R, Clevers H (2017) Wnt/β-catenin signaling. Disease emerging therapeutic modalities. Cell 169(6):985–999

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  75. Oh S, Gwak J, Park S, Yang CS (2014) Green tea polyphenol EGCG suppresses Wnt/β-catenin signaling by promoting GSK-3β- and PP2A-independent β-catenin phosphorylation/degradation. Biofactors 40(6):586–595

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. Omodanisi EI, Aboua YG, Oguntibeju OO (2017) Assessment of the anti-hyperglycaemic, anti-inflammatory and antioxidant activities of the methanol extract of Moringa Oleifera in diabetes-induced nephrotoxic male Wistar rats. Molecules 22(4):439

    PubMed Central  Article  CAS  Google Scholar 

  77. Palomer E, Buechler J, Salinas PC (2019) Wnt signaling deregulation in the aging and Alzheimer’s brain. Front Cell Neurosci 13:227

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Panche AN, Diwan AD, Chandra SR (2016) Flavonoids: an overview. J Nutr Sci 5:e47

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. Pandey KB, Rizvi SI (2009) Plant polyphenols as dietary antioxidants in human health and disease. Oxid Med Cell Longev 2(5):270–278

    PubMed  PubMed Central  Article  Google Scholar 

  80. Pandima Devi K, Rajavel T, Daglia M, Nabavi SF, Bishayee A, Nabavi SM (2017) Targeting miRNAs by polyphenols: Novel therapeutic strategy for cancer. Semin Cancer Biol 46:146–157

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  81. Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H, Ke H, Rehmann H, Taussig R, Brown AL, Kim MK, Beaven MA, Burgin AB, Manganiello V, Chung JH (2012) Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP. Cell 148(3):421–433

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. Pazoki-Toroudi H, Amani H, Ajami M, Nabavi SF, Braidy N, Kasi PD, Nabavi SM (2016) Targeting mTOR signaling by polyphenols: a new therapeutic target for ageing. Ageing Res Rev 31:55–66

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. Pyott SM, Tran TT, Leistritz DF, Pepin MG, Mendelsohn NJ, Temme RT, Fernandez BA, Elsayed SM, Elsobky E, Verma I, Nair S, Turner EH, Smith JD, Jarvik GP, Byers PH (2013) WNT1 mutations in families affected by moderately severe and progressive recessive osteogenesis imperfecta. Am J Hum Genet 92(4):590–597

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. Rahimifard M, Maqbool F, Moeini-Nodeh S, Niaz K, Abdollahi M, Braidy N, Nabavi SM, Nabavi SF (2017) Targeting the TLR4 signaling pathway by polyphenols: a novel therapeutic strategy for neuroinflammation. Ageing Res Rev 36:11–19

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  85. Rattan SI (2008) Hormesis in aging. Ageing Res Rev 7(1):63–78

    PubMed  Article  PubMed Central  Google Scholar 

  86. Reboredo-Rodríguez P, Figueiredo-González M, González-Barreiro C, Simal-Gándara J, Salvador MD, Cancho-Grande B, Fregapane G (2017) State of the art on functional virgin olive oils enriched with bioactive compounds and their properties. Int J Mol Sci 18(3):668

    PubMed Central  Article  CAS  Google Scholar 

  87. Rogan MR, Patterson LL, Wang JY, McBride JW (2019) Bacterial manipulation of Wnt signaling: a host-pathogen tug-of-Wnt. Front Immunol 10:2390

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Rogers SA, Chen F, Talcott MR, Faulkner C, Thomas JM, Thevis M, Hammerman MR (2007) Long-term engraftment following transplantation of pig pancreatic primordia into non-immunosuppressed diabetic rhesus macaques. Xenotransplantation 14(6):591–602

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA (2000) Inhibition of adipogenesis by Wnt signaling. Science 289(5481):950–953

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. Russo GL, Spagnuolo C, Russo M, Tedesco I, Moccia S, Cervellera C (2020) Mechanisms of aging and potential role of selected polyphenols in extending healthspan. Biochem Pharmacol 173:113719

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  91. Sawda C, Moussa C, Turner RS (2017) Resveratrol for Alzheimer’s disease. Ann N Y Acad Sci 1403(1):142–149

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. Serreli G, Deiana M (2020) Extra virgin olive oil polyphenols: modulation of cellular pathways related to oxidant species and inflammation in aging. Cells 9(2):478

    CAS  PubMed Central  Article  Google Scholar 

  93. Sharma A, Kaur M, Katnoria JK, Nagpal AK (2018) Polyphenols in food: cancer prevention and apoptosis induction. Curr Med Chem 25(36):4740–4757

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  94. Sharma N, Nehru B (2018) Curcumin affords neuroprotection and inhibits α-synuclein aggregation in lipopolysaccharide-induced Parkinson’s disease model. Inflammopharmacology 26(2):349–360

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. Shaw OM, Hurst RD, Harper JL (2016) Boysenberry ingestion supports fibrolytic macrophages with the capacity to ameliorate chronic lung remodeling. Am J Physiol Lung Cell Mol Physiol 311(3):L628–L638

    PubMed  Article  PubMed Central  Google Scholar 

  96. Shim SS, Stutzmann GE (2016) Inhibition of glycogen synthase kinase-3: an emerging target in the treatment of traumatic brain injury. J Neurotrauma 33(23):2065–2076

    PubMed  Article  PubMed Central  Google Scholar 

  97. Shinohara M, Tachibana M, Kanekiyo T, Bu G (2017) Role of LRP1 in the pathogenesis of Alzheimer’s disease: evidence from clinical and preclinical studies. J Lipid Res 58(7):1267–1281

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. Singh S, Mishra A, Mohanbhai SJ, Tiwari V, Chaturvedi RK, Khurana S, Shukla S (2018) Axin-2 knockdown promote mitochondrial biogenesis and dopaminergic neurogenesis by regulating Wnt/β-catenin signaling in rat model of Parkinson’s disease. Free Radic Biol Med 129:73–87

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  99. Srivastava NS, Srivastava RAK (2019) Curcumin and quercetin synergistically inhibit cancer cell proliferation in multiple cancer cells and modulate Wnt/β-catenin signaling and apoptotic pathways in A375 cells. Phytomedicine 52:117–128

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Tian L, Song Z, Shao W, Du WW, Zhao LR, Zeng K, Yang BB, Jin T (2017) Curcumin represses mouse 3T3-L1 cell adipogenic differentiation via inhibiting miR-17-5p and stimulating the Wnt signalling pathway effector Tcf7l2. Cell Death Dis 8(1):e2559

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Tiwari SK, Agarwal S, Seth B, Yadav A, Nair S, Bhatnagar P, Karmakar M, Kumari M, Chauhan LK, Patel DK, Srivastava V, Singh D, Gupta SK, Tripathi A, Chaturvedi RK, Gupta KC (2014) Curcumin-loaded nanoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer’s disease model via canonical Wnt/β-catenin pathway. ACS Nano 8(1):76–103

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. Tsai Y-M, Chien C-F, Lin L-C, Tsai T-H (2011) Curcumin and its nano-formulation: the kinetics of tissue distribution and blood–brain barrier penetration. Int J Pharm 416(1):331–338

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  103. Tuo J, Wang Y, Cheng R, Li Y, Chen M, Qiu F, Qian H, Shen D, Penalva R, Xu H, Ma JX, Chan CC (2015) Wnt signaling in age-related macular degeneration: human macular tissue and mouse model. J Transl Med 13:330

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. Vakili S, Zal F, Mostafavi-Pour Z, Savardashtaki A, Koohpeyma F (2021) Quercetin and vitamin E alleviate ovariectomy-induced osteoporosis by modulating autophagy and apoptosis in rat bone cells. J Cell Physiol 236(5):3495–3509

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  105. Vallée A, Lecarpentier Y, Vallée JN (2019) Curcumin: a therapeutic strategy in cancers by inhibiting the canonical WNT/β-catenin pathway. J Exp Clin Cancer Res 38(1):323

    PubMed  PubMed Central  Article  Google Scholar 

  106. Vargas AJ, Burd R (2010) Hormesis and synergy: pathways and mechanisms of quercetin in cancer prevention and management. Nutr Rev 68(7):418–428

    PubMed  Article  PubMed Central  Google Scholar 

  107. Voulgaropoulou SD, van Amelsvoort T, Prickaerts J, Vingerhoets C (2019) The effect of curcumin on cognition in Alzheimer’s disease and healthy aging: a systematic review of pre-clinical and clinical studies. Brain Res 1725:146476

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. Wang D, Dong X, Wang C (2018) Honokiol ameliorates amyloidosis and neuroinflammation and improves cognitive impairment in Alzheimer’s disease transgenic mice. J Pharmacol Exp Ther 366(3):470–478

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  109. Wang HD, Shi YM, Li L, Guo JD, Zhang YP, Hou SX (2013) Treatment with resveratrol attenuates sublesional bone loss in spinal cord-injured rats. Br J Pharmacol 170(4):796–806

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. Wang JY, Wang X, Wang XJ, Zheng BZ, Wang Y, Wang X, Liang B (2018) Curcumin inhibits the growth via Wnt/β-catenin pathway in non-small-cell lung cancer cells. Eur Rev Med Pharmacol Sci 22(21):7492–7499

    PubMed  PubMed Central  Google Scholar 

  111. Wang M, Li Y, Ni C, Song G (2017) Honokiol attenuates oligomeric amyloid β1-42-induced Alzheimer’s disease in mice through attenuating mitochondrial apoptosis and inhibiting the nuclear factor Kappa-B signaling pathway. Cell Physiol Biochem 43(1):69–81

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  112. Wang YL, Ju B, Zhang YZ, Yin HL, Liu YJ, Wang SS, Zeng ZL, Yang XP, Wang HT, Li JF (2017) Protective effect of curcumin against oxidative stress-induced injury in rats with Parkinson’s disease through the Wnt/ β-catenin signaling pathway. Cell Physiol Biochem 43(6):2226–2241

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  113. Wang Z, Liu CH, Huang S, Chen J (2019) Wnt Signaling in vascular eye diseases. Prog Retin Eye Res 70:110–133

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. Weinert BT, Timiras PS (2003) Invited review: theories of aging.  J Appl Physiol (1985) 95(4):1706–1716

    CAS  Article  Google Scholar 

  115. Weisberg SP, Leibel R, Tortoriello DV (2008) Dietary curcumin significantly improves obesity-associated inflammation and diabetes in mouse models of diabesity. Endocrinology 149(7):3549–3558

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. Wu D, Pan W (2010) GSK3: a multifaceted kinase in Wnt signaling. Trends Biochem Sci 35(3):161–168

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. Xing Z, Wang HY, Su WY, Liu YF, Wang XX, Zhan P, Lv TF, Song Y (2018) Wnt3 knockdown sensitizes human non-small cell type lung cancer (NSCLC) cells to cisplatin via regulating the cell proliferation and apoptosis. Eur Rev Med Pharmacol Sci 22(5):1323–1332

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Xu S, Sun F, Ren L, Yang H, Tian N, Peng S (2017) Resveratrol controlled the fate of porcine pancreatic stem cells through the Wnt/β-catenin signaling pathway mediated by Sirt1. PLoS ONE 12(10):e0187159

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. Yang HC, Wang JY, Bu XY, Yang B, Wang BQ, Hu S, Yan ZY, Gao YS, Han SY, Qu MQ (2019) Resveratrol restores sensitivity of glioma cells to temozolamide through inhibiting the activation of Wnt signaling pathway. J Cell Physiol 234(5):6783–6800

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  120. Yang M, Li Z, Tao J, Hu H, Li Z, Zhang Z, Cheng F, Sun Y, Zhang Y, Yang J, Wei H, Wu Z (2021) Resveratrol induces PD-L1 expression through snail-driven activation of Wnt pathway in lung cancer cells. J Cancer Res Clin Oncol 147(4):1101–1113

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Yang Y (2012) Wnt signaling in development and disease. Cell Biosci 2(1):14

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. Yen HY, Tsao CW, Lin YW, Kuo CC, Tsao CH, Liu CY (2019) Regulation of carcinogenesis and modulation through Wnt/β-catenin signaling by curcumin in an ovarian cancer cell line. Sci Rep 9(1):17267

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  123. Yu T, Wang Z, You X, Zhou H, He W, Li B, Xia J, Zhu H, Zhao Y, Yu G, Xiong Y, Yang Y (2020) Resveratrol promotes osteogenesis and alleviates osteoporosis by inhibiting p53. Aging 12(11):10359–10369

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. Yuan Z, Min J, Zhao Y, Cheng Q, Wang K, Lin S, Luo J, Liu H (2018) Quercetin rescued TNF-alpha-induced impairments in bone marrow-derived mesenchymal stem cell osteogenesis and improved osteoporosis in rats. Am J Transl Res 10(12):4313–4321

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Zhang C, Wang HJ, Bao QC, Wang L, Guo TK, Chen WL, Xu LL, Zhou HS, Bian JL, Yang YR, Sun HP, Xu XL, You QD (2016) NRF2 promotes breast cancer cell proliferation and metastasis by increasing RhoA/ROCK pathway signal transduction. Oncotarget 7(45):73593–73606

    PubMed  PubMed Central  Article  Google Scholar 

  126. Zhang G, Chen L, Liu J, Jin Y, Lin Z, Du S, Fu Z, Chen T, Qin Y, Sui F, Jiang Y (2020) HIF-1α/microRNA-128-3p axis protects hippocampal neurons from apoptosis via the Axin1-mediated Wnt/β-catenin signaling pathway in Parkinson’s disease models. Aging 12(5):4067–4081

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Zhang N, Yan F, Liang X, Wu M, Shen Y, Chen M, Xu Y, Zou G, Jiang P, Tang C, Zheng H, Dai Z (2018) Localized delivery of curcumin into brain with polysorbate 80-modified cerasomes by ultrasound-targeted microbubble destruction for improved Parkinson’s disease therapy. Theranostics 8(8):2264–2277

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. Zhang X, Yin WK, Shi XD, Li Y (2011) Curcumin activates Wnt/β-catenin signaling pathway through inhibiting the activity of GSK-3β in APPswe transfected SY5Y cells. Eur J Pharm Sci 42(5):540–546

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  129. Zhao Q, Ning P, Yang X, Shi C, Xu Y, Shen Q, Huang H, Xie D, Chen Y, Xu Y (2021) LRP10 mutations may correlate with sporadic Parkinson’s disease in China. Mol Neurobiol 58(3):1212–1216

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  130. Zhou Y, Park SY, Su J, Bailey K, Ottosson-Laakso E, Shcherbina L, Oskolkov N, Zhang E, Thevenin T, Fadista J, Bennet H, Vikman P, Wierup N, Fex M, Rung J, Wollheim C, Nobrega M, Renström E, Groop L, Hansson O (2014) TCF7L2 is a master regulator of insulin production and processing. Hum Mol Genet 23(24):6419–6431

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. Zhu JY, Yang X, Chen Y, Jiang Y, Wang SJ, Li Y, Wang XQ, Meng Y, Zhu MM, Ma X, Huang C, Wu R, Xie CF, Li XT, Geng SS, Wu JS, Zhong CY, Han HY (2017) Curcumin suppresses lung cancer stem cells via inhibiting Wnt/β-catenin and sonic hedgehog pathways. Phytother Res 31(4):680–688

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Affiliations

Authors

Contributions

PMD, FS, MAM, and HM contributed in conception, design and drafting of the manuscript. BY and ZA contributed in data collection and manuscript drafting. All authors approved the final version for submission.

Corresponding authors

Correspondence to Zatollah Asemi or Bahman Yousefi.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Maleki Dana, P., Sadoughi, F., Mansournia, M.A. et al. Targeting Wnt signaling pathway by polyphenols: implication for aging and age-related diseases. Biogerontology 22, 479–494 (2021). https://doi.org/10.1007/s10522-021-09934-x

Download citation

Keywords

  • Aging
  • Polyphenol
  • Wnt
  • Diabetes
  • Cancer
  • Neurodegenerative disease
  • Osteopenia