Targeting mTOR signaling by polyphenols: A new therapeutic target for ageing

Ageing Research Reviews

Volumn 31, Issue , 2016, Pages 55-66

  Pazoki Toroudi, Hamidreza ^a   Amani, Hamed ^a   Ajami, Marjan ^b   Nabavi, Seyed Fazel ^c   Braidy, Nady ^d   Kasi, Pandima Devi ^e   Nabavi, Seyed Mohammad ^c  

^a IRAN UNIVERSITY OF MEDICAL SCIENCES   (Iran)

^b SHAHID BEHESHTI UNIVERSITY OF MEDICAL SCIENCES   (Iran)

^c BAQIYATALLAH UNIVERSITY OF MEDICAL SCIENCES   (Iran)

^d UNIVERSITY OF NEW SOUTH WALES   (Australia)

^e ALAGAPPA UNIVERSITY   (India)

Author keywords

Ageing; Flavonoid; mTOR; Polyphenol

Indexed keywords

MAMMALIAN TARGET OF RAPAMYCIN; POLYPHENOL; MTOR PROTEIN, HUMAN; RAPAMYCIN; TARGET OF RAPAMYCIN KINASE;

AGING; DEGENERATION; DRUG MECHANISM; ENZYME INHIBITION; HUMAN; LIFE EXTENSION; LONGEVITY; MODULATION; MOLECULAR PATHOLOGY; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; ANIMAL; CELL AGING; DRUG EFFECTS; METABOLISM; PHYSIOLOGY;

AGING; ANIMALS; CELL AGING; HUMANS; LONGEVITY; POLYPHENOLS; SIGNAL TRANSDUCTION; SIROLIMUS; TOR SERINE-THREONINE KINASES;

EID: 84979743554     PISSN: 15681637     EISSN: 18729649     Source Type: Journal    
DOI: 10.1016/j.arr.2016.07.004     Document Type: Review

References (192)

1. Adhami, V.M., Syed, D.N., Khan, N., Mukhtar, H., Dietary flavonoid fisetin: a novel dual inhibitor of PI3K/Akt and mTOR for prostate cancer management. Biochem. Pharmacol. 84:10 (2012), 1277–1281.
2. Alañón, M., Castro-Vázquez, L., Díaz-Maroto, M., Gordon, M., Pérez-Coello, M., A study of the antioxidant capacity of oak wood used in wine ageing and the correlation with polyphenol composition. Food Chem. 128:4 (2011), 997–1002.
3. Averett, C.A., Bhardwaj, A., Arora, S., Srivastava, S., Singh, S., Carter, J.E., Singh, A.P., Honokiol attenuates stemness, growth and metastasis of pancreatic tumor cells: a novel natural agent for therapy and prevention. Cancer Res., 76, 2016, 10.1158/1538-7445.fbcr15-b02.
4. Aylett, C.H., Sauer, E., Imseng, S., Boehringer, D., Hall, M.N., Ban, N., Maier, T., Architecture of human mTOR complex 1. Science 351:6268 (2016), 48–52.
5. Badiola, I., Santaolalla, F., Garcia-Gallastegui, P., Sánchez-del Rey, A., Unda, F., Ibarretxe, G., Biomolecular bases of the senescence process and cancer: a new approach to oncological treatment linked to ageing. Ageing Res. Rev. 23:Pt B (2015), 125–138.
6. Baker, D.J., Wijshake, T., Tchkonia, T., LeBrasseur, N.K., Childs, B.G., van de Sluis, B., Kirkland, J.L., van Deursen, J.M., Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:7372 (2011), 232–236.
7. Baker, D.J., Childs, B.G., Durik, M., Wijers, M.E., Sieben, C.J., Zhong, J., Saltness, R.A., Jeganathan, K.B., Verzosa, G.C., Pezeshki, A., Khazaie, K., Miller, J.D., van Deursen, J.M., Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530:7589 (2016), 184–189.
8. Banerjee, N., Kim, H., Talcott, S., Mertens-Talcott, S., Pomegranate polyphenolics suppressed azoxymethane-induced colorectal aberrant crypt foci and inflammation: possible role of miR-126/VCAM-1 and miR-126/PI3K/AKT/mTOR. Carcinogenesis 34:12 (2013), 2814–2822.
9. Barger, J.L., Kayo, T., Vann, J.M., Arias, E.B., Wang, J., Hacker, T.A., Wang, Y., Raederstorff, D., Morrow, J.D., Leeuwenburgh, C., A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS One, 3(6), 2008, e2264.
10. Bartke, A., Westbrook, R., Metabolic characteristics of long-lived mice. Front. Genet., 3, 2012, 288.
11. Beevers, C.S., Chen, L., Liu, L., Luo, Y., Webster, N.J., Huang, S., Curcumin disrupts the Mammalian target of rapamycin-raptor complex. Cancer Res. 69:3 (2009), 1000–1008.
12. Bender, A., Stewart, A.F., Good news for the ageing beta cell. Diabetologia 57:2 (2014), 265–269.
13. Bishayee, A., Cancer prevention and treatment with resveratrol: from rodent studies to clinical trials. Cancer Prev. Res. 2:5 (2009), 409–418.
14. Bitzer, M., Wiggins, J., Aging biology in the kidney. Adv. Chronic Kidney Dis. 23:1 (2016), 12–18.
15. Boots, A.W., Drent, M., de Boer, V.C., Bast, A., Haenen, G.R., Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis. Clin. Nutr. 30:4 (2011), 506–512.
16. Brown, M.K., Naidoo, N., The endoplasmic reticulum stress response in aging and age-related diseases. Front. Physiol., 3, 2012, 263.
17. Brown, M.K., Chan, M.T., Zimmerman, J.E., Pack, A.I., Jackson, N.E., Naidoo, N., Aging induced endoplasmic reticulum stress alters sleep and sleep homeostasis. Neurobiol. Aging (Milano) 35:6 (2014), 1431–1441.
18. Brown, D., Antibiotic resistance breakers: can repurposed drugs fill the antibiotic discovery void?. Nature Rev. Drug Discovery 14:12 (2015), 821–832.
19. Bunel, V., Antoine, M.H., Stevigny, C., Nortier, J., Duez, P., New in vitro insights on a cell death pathway induced by magnolol and honokiol in aristolochic acid tubulotoxicity. Food Chem. Toxicol. 87 (2016), 77–87.
20. Carr, T.D., Feehan, R.P., Hall, M.N., Rüegg, M.A., Shantz, L.M., Conditional disruption of rictor demonstrates a direct requirement for mTORC2 in skin tumor development and continued growth of established tumors. Carcinogenesis 36:4 (2015), 487–497.
21. Cerella, C., Gaigneaux, A., Dicato, M., Diederich, M., Antagonistic role of natural compounds in mTOR-mediated metabolic reprogramming. Cancer Lett. 356:2 (2015), 251–262.
22. Cerella, C., Grandjenette, C., Dicato, M., Diederich, M., Roles of apoptosis and cellular senescence in cancer and Aging. Curr. Drug Targets 17:4 (2016), 405–415.
23. Chalil, S., Jaspers, R.T., Manders, R.J., Klein-Nulend, J., Bakker, A.D., Deldicque, L., Increased endoplasmic reticulum stress in mouse osteocytes with aging alters cox-2 response to mechanical stimuli. Calcif. Tissue Int. 96:2 (2015), 123–128.
24. Chamcheu, J., Chaves-Rodriquez, M., Siddiqui, I., Adhami, V., Syed, D.N., Dodwad, S., Mukhtar, H., Fisetin, a small molecule and a natural inhibitor of mTOR for treating psoriasis. J. Invest. Dermatol., 135, 2015, S96.
25. Charles, A.L., Meyer, A., Dal-Ros, S., Auger, C., Keller, N., Ramamoorthy, T.G., Zoll, J., Metzger, D., Schini-Kerth, V., Geny, B., Polyphenols prevent ageing-related impairment in skeletal muscle mitochondrial function through decreased reactive oxygen species production. Exp. Physiol. 98:2 (2013), 536–545.
26. Chen, H., Zhu, G.M., Liu, N., Zhang, W.W., Low-dose tissue plasminogen activator is as effective as standard tissue plasminogen activator administration for the treatment of acute ischemic stroke. Curr. Neurovasc. Res. 11:1 (2014), 62–67.
27. Chen, S., Zhou, N., Zhang, Z., Li, W., Zhu, W., Resveratrol induces cell apoptosis in adipocytes via AMPK activation. Biochem. Biophys. Res. Commun. 457:4 (2015), 608–613.
28. Chen, X., Dong, X.S., Gao, H.Y., Jiang, Y.F., Jin, Y.L., Chang, Y.Y., Chen, L.Y., Wang, J.H., Suppression of HSP27 increases the anti-tumor effects of quercetin in human leukemia U937 cells. Mol. Med. Rep 13:1 (2016), 689–696.
29. Cheng, A.L., Hsu, C.H., Lin, J.K., Hsu, M.M., Ho, Y.F., Shen, T.S., Ko, J.Y., Lin, J.T., Lin, B.R., Ming-Shiang, W., Yu, H.S., Jee, S.H., Chen, G.S., Chen, T.M., Chen, C.A., Lai, M.K., Pu, Y.S., Pan, M.H., Wang, Y.J., Tsai, C.C., Hsieh, C.Y., Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 21:4B (2001), 2895–2900.
30. Chien, P.T.Y., Lin, C.C., Hsiao, L.D., Yang, C.M., c Src/Pyk2/EGFR/PI3 K/Akt/CREB-activated pathway contributes to human cardiomyocyte hypertrophy: role of COX-2 induction. Mol. Cell. Endocrinol. 409 (2015), 59–72.
31. Chiu, C.T., Hsuan, S.W., Lin, H.H., Hsu, C.C., Chou, F.P., Chen, J.H., Hibiscus sabdariffa leaf polyphenolic extract induces human melanoma cell death, apoptosis, and autophagy. J. Food Sci. 80:3 (2015), H649–H658.
32. Conquer, J.A., Maiani, G., Azzini, E., Raguzzini, A., Holub, B.J., Supplementation with quercetin markedly increases plasma quercetin concentration without effect on selected risk factors for heart disease in healthy subjects. J. Nutr. 128:3 (1998), 593–597.
33. Dalle Pezze, P., Sonntag, A.G., Thien, A., Prentzell, M.T., Gödel, M., Fischer, S., Neumann-Haefelin, E., Huber, T.B., Baumeister, R., Shanley, D.P., A dynamic network model of mTOR signaling reveals TSC-independent mTORC2 regulation. Sci. Signal, 5(217), 2012, ra25.
34. Demidenko, Z.N., Zubova, S.G., Bukreeva, E.I., Pospelov, V.A., Pospelova, T.V., Blagosklonny, M.V., Rapamycin decelerates cellular senescence. Cell Cycle 8:12 (2009), 1888–1895.
35. Dibble, C.C., Cantley, L.C., Regulation of mTORC1 by PI3K signaling. Trends Cell Biol. 25:9 (2015), 545–555.
36. Eckel-Mahan, K.L., Phan, T., Han, S., Wang, H., Chan, G.C., Scheiner, Z.S., Storm, D.R., Circadian oscillation of hippocampal MAPK activity and cAMP: implications for memory persistence. Nature Neurosci. 11:9 (2008), 1074–1082.
37. Efeyan, A., Comb, W.C., Sabatini, D.M., Nutrient-sensing mechanisms and pathways. Nature 517:7534 (2015), 302–310.
38. Egert, S., Boesch-Saadatmandi, C., Wolffram, S., Rimbach, G., Muller, M.J., Serum lipid and blood pressure responses to quercetin vary in overweight patients by apolipoprotein E genotype. J. Nutr. 140:2 (2010), 278–284.
39. Ferry, D.R., Smith, A., Malkhandi, J., Fyfe, D.W., deTakats, P.G., Anderson, D., Baker, J., Kerr, D.J., Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin. Cancer Res. 2:4 (1996), 659–668.
40. Fischer, F., Filippis, C., Osiewacz, H.D., RCF1-dependent respiratory supercomplexes are integral for lifespan-maintenance in a fungal ageing model. Sci. Rep., 5, 2015, 12697.
41. Gabor, M., Eperjessy, E., Antibacterial effect of fisetin and fisetinidin. Nature, 212(5067), 1966, 1273.
42. Garcia-Villalba, R., Larrosa, M., Possemiers, S., Tomas-Barberan, F.A., Espin, J.C., Bioavailability of phenolics from an oleuropein-rich olive (Olea europaea) leaf extract and its acute effect on plasma antioxidant status: comparison between pre- and postmenopausal women. Eur. J. Nutr. 53:4 (2014), 1015–1027.
43. George, V.C., Promising tumor inhibiting potentials of fisetin through PI3K/AKT/mTOR pathway. Am. J. Transl. Res. 8:2 (2016), 1293–1294.
44. Ghosh, A.K., Garg, S.K., Mau, T., O'Brien, M., Liu, J., Yung, R., Elevated endoplasmic reticulum stress response contributes to adipose tissue inflammation in aging. J. Gerontol. Ser. A: Biol. Sci. Med. Sci. 70:11 (2014), 1320–1329.
45. Goldberg, D.M., Yan, J., Soleas, G.J., Absorption of three wine-related polyphenols in three different matrices by healthy subjects. Clin. Biochem. 36:1 (2003), 79–87.
46. Gollapudi, P., Hasegawa, L.S., Eastmond, D.A., A comparative study of the aneugenic and polyploidy-inducing effects of fisetin and two model Aurora kinase inhibitors. Mutat. Res. Genet. Toxicol. Environ. Mutagen 767 (2014), 37–43.
47. Gong, C.Y., Wei, X.W., Wang, X.H., Wang, Y.J., Guo, G., Mao, Y.Q., Luo, F., Qian, Z.Y., Biodegradable self-assembled PEG-PCL-PEG micelles for hydrophobic honokiol delivery: I: Preparation and characterization. Nanotechnology, 21(21), 2010, 215103.
48. Gopaul, R., Knaggs, H.E., Lephart, E.D., Biochemical investigation and gene analysis of equol: a plant and soy-derived isoflavonoid with antiaging and antioxidant properties with potential human skin applications. Biofactors 38:1 (2012), 44–52.
49. Gordon, B.S., Kazi, A.A., Coleman, C.S., Dennis, M.D., Chau, V., Jefferson, L.S., Kimball, S.R., RhoA modulates signaling through the mechanistic target of rapamycin complex 1 (mTORC1) in mammalian cells. Cell. Signal. 26:3 (2014), 461–467.
50. Gou, M.L., Zheng, L., Peng, X.Y., Men, K., Zheng, X.L., Zeng, S., Guo, G., Luo, F., Zhao, X., Chen, L.J., Wei, Y.Q., Qian, Z.Y., Poly(epsilon-caprolactone)-poly(ethylene glycol)−poly(epsilon-caprolactone) (PCL-PEG-PCL) nanoparticles for honokiol delivery in vitro. Int. J. Pharm. 375:1-2 (2009), 170–176.
51. Gou, M.L., Gong, C.Y., Zhang, J., Wang, X.H., Wang, X.H., Gu, Y.C., Guo, G., Chen, L.J., Luo, F., Zhao, X., Wei, Y.Q., Qian, Z.Y., Polymeric matrix for drug delivery: honokiol-loaded PCL-PEG-PCL nanoparticles in PEG-PCL-PEG thermosensitive hydrogel. J. Biomed. Mater. Res. Part A 93A:1 (2010), 219–226.
52. Guo, S.Y., Long, M.Z., Li, X.Z., Zhu, S.S., Zhang, M., Yang, Z.J., Curcumin activates autophagy and attenuates oxidative damage in EA.hy926 cells via the Akt/mTOR pathway. Mol. Med. Rep. 13:3 (2016), 2187–2193.
53. Gupta, S.C., Patchva, S., Aggarwal, B.B., Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 15:1 (2013), 195–218.
54. Haddad, A.Q., Fleshner, N., Nelson, C., Saour, B., Musquera, M., Venkateswaran, V., Klotz, L., Antiproliferative mechanisms of the flavonoids 2,2'-Dihydroxychalcone and fisetin in human prostate cancer cells. Nutr. Cancer 62:5 (2010), 668–681.
55. Hadrich, F., Garcia, M., Maalej, A., Moldes, M., Isoda, H., Feve, B., Sayadi, S., Oleuropein activated AMPK and induced insulin sensitivity in C2C12 muscle cells. Life Sci. 151 (2016), 167–173.
56. He, H., Liu, X., Lv, L., Liang, H., Leng, B., Zhao, D., Zhang, Y., Du, Z., Chen, X., Li, S., Calcineurin suppresses AMPK-dependent cytoprotective autophagy in cardiomyocytes under oxidative stress. Cell. Death. Dis., 5(1), 2014, e997.
57. Hoek-van den Hil, E.F., van Schothorst, E.M., van der Stelt, I., Swarts, H.J., van Vliet, M., Amolo, T., Vervoort, J.J., Venema, D., Hollman, P.C., Rietjens, I.M., Keijer, J., Direct comparison of metabolic health effects of the flavonoids quercetin, hesperetin, epicatechin, apigenin and anthocyanins in high-fat-diet-fed mice. Genes Nutr., 4, 2015, 469.
58. Hsieh, C.F., Tsuei, Y.W., Liu, C.W., Kao, C.C., Shih, L.J., Ho, L.T., Wu, L.Y., Wu, C.P., Tsai, P.H., Chang, H.H., Ku, H.C., Kao, Y.H., Green tea epigallocatechin gallate inhibits insulin stimulation of adipocyte glucose uptake via the 67-kilodalton laminin receptor and AMP-activated protein kinase pathways. Planta Med. 76:15 (2010), 1694–1698.
59. Hukelmann, J.L., Anderson, K.E., Sinclair, L.V., Grzes, K.M., Murillo, A.B., Hawkins, P.T., Stephens, L.R., Lamond, A.I., Cantrell, D.A., The cytotoxic T cell proteome and its shaping by the kinase mTOR. Nat. Immunol. 17:1 (2016), 104–112.
60. Hwang, J.T., Kwon, D.Y., Yoon, S.H., AMP-activated protein kinase: a potential target for the diseases prevention by natural occurring polyphenols. New Biotechnol. 26:1 (2009), 17–22.
61. Hytti, M., Piippo, N., Korhonen, E., Honkakoski, P., Kaarniranta, K., Kauppinen, A., Fisetin and luteolin protect human retinal pigment epithelial cells from oxidative stress-induced cell death and regulate inflammation. Sci. Rep., 5, 2015, 17645.
62. Inkielewicz-Stepniak, I., Radomski, M.W., Wozniak, M., Fisetin prevents fluoride- and dexamethasone-induced oxidative damage in osteoblast and hippocampal cells. Food Chem. Toxicol. 50:3-4 (2012), 583–589.
63. Ishisaka, A., Ichikawa, S., Sakakibara, H., Piskula, M.K., Nakamura, T., Kato, Y., Ito, M., Miyamoto, K., Tsuji, A., Kawai, Y., Terao, J., Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats. Free Radic. Biol. Med. 51:7 (2011), 1329–1336.
64. Isik, A.T., Celik, T., Ulusoy, G., Ongoru, O., Elibol, B., Doruk, H., Bozoglu, E., Kayir, H., Mas, M.R., Akman, S., Curcumin ameliorates impaired insulin/IGF signalling and memory deficit in a streptozotocin-treated rat model. Age (Dordr) 31:1 (2009), 39–49.
65. Jeong, H.U., Kim, J.H., Kong, T.Y., Choi, W.G., Lee, H.S., Comparative metabolism of honokiol in mouse, rat, dog, monkey, and human hepatocytes. Arch. Pharm. Res. 39:4 (2016), 516–530.
66. Johnson, S.M., Gulhati, P., Arrieta, I., Wang, X., Uchida, T., Gao, T., Evers, B.M., Curcumin inhibits proliferation of colorectal carcinoma by modulating Akt/mTOR signaling. Anticancer Res. 29:8 (2009), 3185–3190.
67. Johnson, S.C., Rabinovitch, P.S., Kaeberlein, M., mTOR is a key modulator of ageing and age-related disease. Nature 493:7432 (2013), 338–345.
68. Kaeberlein, M., mTOR inhibition: from aging to autism and beyond. Scientifica, 2013, 2013, 849186.
69. Kakkar, V., Singh, S., Singla, D., Kaur, I.P., Exploring solid lipid nanoparticles to enhance the oral bioavailability of curcumin. Mol. Nutr. Food Res. 55:3 (2011), 495–503.
70. Kaneda, A., Nonaka, A., Fujita, T., Yamanaka, R., Fujimoto, M., Miyazono, K., Aburatani, H., Epigenomic regulation of smad1 signaling during cellular senescence induced by ras activation. Methods Mol. Biol. 1344 (2016), 341–353.
71. Kanfi, Y., Naiman, S., Amir, G., Peshti, V., Zinman, G., Nahum, L., Bar-Joseph, Z., Cohen, H.Y., The sirtuin SIRT6 regulates lifespan in male mice. Nature 483:7388 (2012), 218–221.
72. Kelkel, M., Jacob, C., Dicato, M., Diederich, M., Potential of the dietary antioxidants resveratrol and curcumin in prevention and treatment of hematologic malignancies. Molecules 15:10 (2010), 7035–7074.
73. Kenyon, C.J., The genetics of ageing. Nature 464:7288 (2010), 504–512.
74. Kerdiles, Y.M., Beisner, D.R., Tinoco, R., Dejean, A.S., Castrillon, D.H., DePinho, R.A., Hedrick, S.M., Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat. Immunol. 10:2 (2009), 176–184.
75. Khan, N., Syed, D.N., Ahmad, N., Mukhtar, H., Fisetin: a dietary antioxidant for health promotion. Antioxid. Redox Signal. 19:2 (2013), 151–162.
76. Kim, M.K., Park, K.S., Yeo, W.S., Choo, H., Chong, Y., In vitro solubility, stability and permeability of novel quercetin-amino acid conjugates. Bioorg. Med. Chem. 17:3 (2009), 1164–1171.
77. Kim, D.B., Shin, G.H., Kim, J.M., Kim, Y.H., Lee, J.H., Lee, J.S., Song, H.J., Choe, S.Y., Park, I.J., Cho, J.H., Antioxidant and anti-ageing activities of citrus-based juice mixture. Food Chem. 194 (2016), 920–927.
78. Klimaszewska-Wisniewska, A., Halas-Wisniewska, M., Tadrowski, T., Gagat, M., Grzanka, D., Grzanka, A., Paclitaxel and the dietary flavonoid fisetin: a synergistic combination that induces mitotic catastrophe and autophagic cell death in A549 non-small cell lung cancer cells. Cancer Cell Int., 16, 2016, 10.
79. Kobylinska, A., Janas, K.M., Health–promoting effect of quercetin in human diet. Postepy Hig Med Dosw (Online) 69 (2015), 51–62.
80. Kondratova, A.A., Kondratov, R.V., The circadian clock and pathology of the ageing brain. Nat. Rev. Neurosci. 13:5 (2012), 325–335.
81. Kyriakakis, E., Princz, A., Tavernarakis, N., Stress responses during ageing: molecular pathways regulating protein homeostasis. Stress Responses Methods Protoc., 2015, 215–234.
82. Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert, P., Elliott, P., Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 127:6 (2006), 1109–1122.
83. Lamming, D.W., Ye, L., Katajisto, P., Goncalves, M.D., Saitoh, M., Stevens, D.M., Davis, J.G., Salmon, A.B., Richardson, A., Ahima, R.S., Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335:6076 (2012), 1638–1643.
84. Lao, C.D., Ruffin, M.T. t., Normolle, D., Heath, D.D., Murray, S.I., Bailey, J.M., Boggs, M.E., Crowell, J., Rock, C.L., Brenner, D.E., Dose escalation of a curcuminoid formulation. BMC Complement. Altern. Med., 6, 2006, 10.
85. Leontieva, O.V., Demidenko, Z.N., Blagosklonny, M.V., Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program). Oncotarget 6:27 (2015), 23238–23248.
86. Leotoing, L., Wauquier, F., Guicheux, J., Miot-Noirault, E., Wittrant, Y., Coxam, V., The polyphenol fisetin protects bone by repressing NF-kappaB and MKP-1-dependent signaling pathways in osteoclasts. PLoS One, 8(7), 2013, e68388.
87. Levine, B., Mizushima, N., Virgin, H.W., Autophagy in immunity and inflammation. Nature 469:7330 (2011), 323–335.
88. Lewis, S., Ageing: synaptic slide into old age. Nat. Rev. Neurosci., 15(9), 2014, 566.
89. Li, J., Qu, W., Cheng, Y., Sun, Y., Jiang, Y., Zou, T., Wang, Z., Xu, Y., Zhao, H., The inhibitory effect of intravesical fisetin against bladder cancer by induction of p53 and down-regulation of NF-kappa B pathways in a rat bladder carcinogenesis model. Basic Clin. Pharmacol. Toxicol. 115:4 (2014), 321–329.
90. Li, J., Ren, J., Liu, X., Jiang, L., He, W., Yuan, W., Yang, J., Dai, C., Rictor/mTORC2 signaling mediates TGFβ1-induced fibroblast activation and kidney fibrosis. Kidney Int. 88:3 (2015), 515–527.
91. Li, M., Hu, G., Chen, Y., Evaluation of the antioxidant capacity of natural polyphenolic compounds using a macrocyclic Ni-(II) complex-catalysed Briggs–Rauscher reaction. Food Chem. 197 (2016), 987–991.
92. Lin, C.L., Huang, H.C., Lin, J.K., Theaflavins attenuate hepatic lipid accumulation through activating AMPK in human HepG2 cells. J. Lipid Res. 48:11 (2007), 2334–2343.
93. Lin, X.L., Liu, M.H., Hu, H.J., Feng, H.R., Fan, X.J., Zou, W.W., Pan, Y.Q., Hu, X.M., Wang, Z., Curcumin enhanced cholesterol efflux by upregulating ABCA1 expression through AMPK-SIRT1-LXRalpha signaling in THP-1 macrophage-derived foam cells. DNA Cell. Biol. 34:9 (2015), 561–572.
94. Lin, C.J., Chang, Y.A., Lin, Y.L., Liu, S.H., Chang, C.K., Chen, R.M., Preclinical effects of honokiol on treating glioblastoma multiforme via G1 phase arrest and cell apoptosis. Phytomedicine 23:5 (2016), 517–527.
95. Liu, Z.P., Zhang, X.P., Cui, W.M., Zhang, X., Li, N., Chen, S.J., Wong, A.W., Roberts, A., Evaluation of short-term and subchronic toxicity of magnolia bark extract in rats. Regul. Toxicol. Pharmacol. 49:3 (2007), 160–171.
96. Liu, Y., Wang, D., Yang, G.J., Shi, Q.S., Feng, F., Comparative pharmacokinetics and brain distribution of magnolol and honokiol after oral administration of Magnolia officinalis cortex extract and its compatibility with other herbal medicines in Zhi-Zi-Hou-Po decoction to rats. Biomed. Chromatogr. 30:3 (2016), 369–375.
97. Lu, W., Kelly, A.L., Miao, S., Emulsion-based encapsulation and delivery systems for polyphenols. Trends Food Sci. Technol. 47 (2016), 1–9.
98. Maher, P., Salgado, K.F., Zivin, J.A., Lapchak, P.A., A novel approach to screening for new neuroprotective compounds for the treatment of stroke. Brain Res. 1173 (2007), 117–125.
99. Maiese, K., Cutting through the complexities of mTOR for the treatment of stroke. Curr. Neurovasc. Res. 11:2 (2014), 177–186.
100. Maiese, K., Driving neural regeneration through the mammalian target of rapamycin. Neural Regener. Res. 9:15 (2014), 1413–1417.
101. Maiese, K., Taking aim at Alzheimer's disease through the mammalian target of rapamycin. Ann. Med. 46:8 (2014), 587–596.
102. Maiese, K., SIRT1 and stem cells: in the forefront with cardiovascular disease, neurodegeneration and cancer. World J. Stem Cells 7:2 (2015), 235–242.
103. Maiese, K., Targeting molecules to medicine with mTOR, autophagy, and neurodegenerative disorders. Br. J. Clin. Pharmacol., 2015, 10.1111/bcp.12804.
104. Makino, T., Shimizu, R., Kanemaru, M., Suzuki, Y., Moriwaki, M., Mizukami, H., Enzymatically modified isoquercitrin, alpha-oligoglucosyl quercetin 3-O-glucoside, is absorbed more easily than other quercetin glycosides or aglycone after oral administration in rats. Biol. Pharm. Bull. 32:12 (2009), 2034–2040.
105. Mannick, J.B., Del Giudice, G., Lattanzi, M., Valiante, N.M., Praestgaard, J., Huang, B., Lonetto, M.A., Maecker, H.T., Kovarik, J., Carson, S., mTOR inhibition improves immune function in the elderly. Sci Transl. Med., 6(268), 2014, 268ra179.
106. McCormick, M.A., Tsai, S.Y., Kennedy, B.K., TOR and ageing: a complex pathway for a complex process. Philos. Trans. R Soc. Lond. B Biol. Sci. 366:1561 (2011), 17–27.
107. Mehrjerdi, F.Z., Aboutaleb, N., Habibey, R., Ajami, M., Soleimani, M., Arabian, M., Niknazar, S., Davoodi, S.H., Pazoki-Toroudi, H., Increased phosphorylation of mTOR is involved in remote ischemic preconditioning of hippocampus in mice. Brain Res. 1526 (2013), 94–101.
108. Mercado, N., Ito, K., Barnes, P.J., Accelerated ageing of the lung in COPD: new concepts. Thorax: Thoraxjnl-, 2015, 2014–206084.
109. Miles, J.M., Rule, A.D., Borlaug, B.A., Use of metformin in diseases of aging. Curr. Diabetes Rep. 14:6 (2014), 1–9.
110. Minino, A.M., Murphy, S.L., Death in the United States, 2010. NCHS Data Brief 99 (2012), 1–8.
111. Mondal, S.C., Singh, P., Kumar, B., Singh, S.K., Gupta, S.K., Verma, A., Ageing and potential anti-aging phytochemicals: an overview. World J. Pharm. Pharm. Sci. 4 (2014), 426–454.
112. Montesanto, A., Geracitano, S., Garasto, S., Fusco, S., Lattanzio, F., Passarino, G., Corsonello, A., The impact of the emerging genomics data on the management of agerelated phenotypes in the context of cellular senescence. Curr. Drug Targets 17:4 (2016), 428–438.
113. Moore, M.N., Do airborne biogenic chemicals interact with the PI3K/Akt/mTOR cell signalling pathway to benefit human health and wellbeing in rural and coastal environments?. Environ. Res. 140 (2015), 65–75.
114. Morselli, E., Maiuri, M.C., Markaki, M., Megalou, E., Pasparaki, A., Palikaras, K., Criollo, A., Galluzzi, L., Malik, S.A., Vitale, I., The life span-prolonging effect of sirtuin-1 is mediated by autophagy. Autophagy 6:1 (2010), 186–188.
115. Mourouti, N., Panagiotakos, D.B., The beneficial effect of a Mediterranean diet supplemented with extra virgin olive oil in the primary prevention of breast cancer among women at high cardiovascular risk in the PREDIMED Trial. Evid. Based Nurs., 2016, 10.1136/ebnurs-2016-102303.
116. Munné-Bosch, S., Senescence: is it universal or not?. Trends Plant Sci. 20:11 (2015), 713–720.
117. Murtaza, I., Adhami, V.M., Hafeez, B.B., Saleem, M., Mukhtar, H., Fisetin, a natural flavonoid, targets chemoresistant human pancreatic cancer AsPC-1 cells through DR3-mediated inhibition of NF-kappaB. Int. J. Cancer 125:10 (2009), 2465–2473.
118. Na, H.J., Park, J.S., Pyo, J.H., Jeon, H.J., Kim, Y.S., Arking, R., Yoo, M.A., Metformin inhibits age-related centrosome amplification in Drosophila midgut stem cells through AKT/TOR pathway. Mech. Ageing Dev. 149 (2015), 8–18.
119. Nie, C., Zhou, J., Qin, X., Shi, X., Zeng, Q., Liu, J., Yan, S., Zhang, L., Reduction of apoptosis by proanthocyanidin-induced autophagy in the human gastric cancer cell line MGC-803. Oncol. Rep. 35:2 (2016), 649–658.
120. O'Neill, C., Kiely, A., Coakley, M., Manning, S., LongSmith, C., Insulin and IGF-1 signalling: longevity, protein homoeostasis and Alzheimer's disease. Biochem. Soc. Transact., 40(4), 2012, 721.
121. Pallauf, K., Giller, K., Huebbe, P., Rimbach, G., Nutrition and healthy ageing: calorie restriction or polyphenol-rich MediterrAsian diet?. Oxid. Med. Cell. Longevity, 2013, 2013, 707421.
122. Park, S.J., Ahmad, F., Philp, A., Baar, K., Williams, T., Luo, H., Ke, H., Rehmann, H., Taussig, R., Brown, A.L., Kim, M.K., Beaven, M.A., Burgin, A.B., Manganiello, V., Chung, J.H., Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148:3 (2012), 421–433.
123. Passtoors, W.M., van den Akker, E.B., Deelen, J., Maier, A.B., van der Breggen, R., Jansen, R., Trompet, S., van Heemst, D., Derhovanessian, E., Pawelec, G., IL7R gene expression network associates with human healthy ageing. Immun. Ageing 12:1 (2015), 1–9.
124. Pegoraro, G., Kubben, N., Wickert, U., Göhler, H., Hoffmann, K., Misteli, T., Ageing-related chromatin defects through loss of the NURD complex. Nat. Cell Biol. 11:10 (2009), 1261–1267.
125. Pergola, P.E., White, C.L., Szychowski, J.M., Talbert, R., del Brutto, O., Castellanos, M., Graves, J.W., Matamala, G., Pretell, E.J., Yee, J., Rebello, R., Zhang, Y., Benavente, O.R., Investigators, S., Achieved blood pressures in the secondary prevention of small subcortical strokes (SPS3) study: challenges and lessons learned. Am. J. Hypertens. 27:8 (2014), 1052–1060.
126. Piao, M.J., Kim, K.C., Chae, S., Keum, Y.S., Kim, H.S., Hyun, J.W., Protective effect of fisetin (3,7,3',4'-tetrahydroxyflavone) against gamma-irradiation-induced oxidative stress and cell damage. Biomol. Ther. (Seoul) 21:3 (2013), 210–215.
127. Prasath, G.S., Subramanian, S.P., Fisetin, a tetra hydroxy flavone recuperates antioxidant status and protects hepatocellular ultrastructure from hyperglycemia mediated oxidative stress in streptozotocin induced experimental diabetes in rats. Food Chem. Toxicol. 59 (2013), 249–255.
128. Prasath, G.S., Sundaram, C.S., Subramanian, S.P., Fisetin averts oxidative stress in pancreatic tissues of streptozotocin-induced diabetic rats. Endocrine 44:2 (2013), 359–368.
129. Proshkina, E.N., Shaposhnikov, M.V., Sadritdinova, A.F., Kudryavtseva, A.V., Moskalev, A.A., Basic mechanisms of longevity: a case study of Drosophila pro-longevity genes. Ageing Res. Rev. 24 (2015), 218–231.
130. Ramos, F.J., Kaeberlein, M., Ageing: a healthy diet for stem cells. Nature 486:7404 (2012), 477–478.
131. Riera, C.E., Dillin, A., Tipping the metabolic scales towards increased longevity in mammals. Nat. Cell Biol. 17:3 (2015), 196–203.
132. Rigacci, S., Miceli, C., Nediani, C., Berti, A., Cascella, R., Pantano, D., Nardiello, P., Luccarini, I., Casamenti, F., Stefani, M., Oleuropein aglycone induces autophagy via the AMPK/mTOR signalling pathway: a mechanistic insight. Oncotarget 6:34 (2015), 35344–35357.
133. Rockenfeller, P., Koska, M., Pietrocola, F., Minois, N., Knittelfelder, O., Sica, V., Franz, J., Carmona-Gutierrez, D., Kroemer, G., Madeo, F., Phosphatidylethanolamine positively regulates autophagy and longevity. Cell Death Different. 22:3 (2015), 499–508.
134. Russo, M., Spagnuolo, C., Tedesco, I., Bilotto, S., Russo, G.L., The flavonoid quercetin in disease prevention and therapy: facts and fancies. Biochem. Pharmacol. 83:1 (2012), 6–15.
135. Sahin, E., DePinho, R.A., Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464:7288 (2010), 520–528.
136. Sahu, B.D., Kumar, J.M., Sistla, R., Fisetin, a dietary flavonoid, ameliorates experimental colitis in mice: relevance of NF-kappaB signaling. J. Nutr. Biochem. 28 (2016), 171–182.
137. Sakaue, Y., Domon, H., Oda, M., Takenaka, S., Kubo, M., Fukuyama, Y., Okiji, T., Terao, Y., Anti-biofilm and bactericidal effects of magnolia bark-derived magnolol and honokiol on Streptococcus mutans. Microbiol. Immunol. 60:1 (2016), 10–16.
138. Schaffer, S., Asseburg, H., Kuntz, S., Muller, W.E., Eckert, G.P., Effects of polyphenols on brain ageing and Alzheimer's disease: focus on mitochondria. Mol. Neurobiol. 46:1 (2012), 161–178.
139. Schreiber, K.H., Ortiz, D., Academia, E.C., Anies, A.C., Liao, C.Y., Kennedy, B.K., Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins. Aging cell 14:2 (2015), 265–273.
140. Sengupta, S., Peterson, T.R., Laplante, M., Oh, S., Sabatini, D.M., mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468:7327 (2010), 1100–1104.
141. Seo, B.R., Min, K.J., Cho, I.J., Kim, S.C., Kwon, T.K., Curcumin significantly enhances dual PI3K/Akt and mTOR inhibitor NVP-BEZ235-induced apoptosis in human renal carcinoma caki cells through down-regulation of p53-dependent bcl-2 expression and inhibition of mcl-1 protein stability (vol 9, e95588, 2014). PLoS One, 11(3), 2016.
142. Sharoar, M., Shi, Q., Ge, Y., He, W., Hu, X., Perry, G., Zhu, X., Yan, R., Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer's disease. Mol. Psychiatry., 2015, 10.1038/mp.2015.181.
143. Shen, Y., Zhang, H., Cheng, L., Wang, L., Qian, H., Qi, X., In vitro and in vivo antioxidant activity of polyphenols extracted from black highland barley. Food Chem. 194 (2016), 1003–1012.
144. Shia, C.S., Tsai, S.Y., Kuo, S.C., Hou, Y.C., Chao, P.D., Metabolism and pharmacokinetics of 3,3',4',7-tetrahydroxyflavone (fisetin), 5-hydroxyflavone, and 7-hydroxyflavone and antihemolysis effects of fisetin and its serum metabolites. J. Agric. Food Chem. 57:1 (2009), 83–89.
145. Sims, J.K., Wade, P.A., Mi-2/NuRD complex function is required for normal S phase progression and assembly of pericentric heterochromatin. Mol. Biol. Cell 22:17 (2011), 3094–3102.
146. Slámová, K., Papoušek, F., Janovská, P., Kopecký, J., Kolář, F., Adverse effects of AMP-activated protein kinase alpha2-subunit deletion and high-fat diet on heart function and ischemic tolerance in aged female mice. Physiol. Res. 65:1 (2015), 33–42.
147. Slack, C., Partridge, L., Genes, pathways and metabolism in ageing. Drug Discov. Today 10:2 (2013), e87–e93.
148. Soleas, G.J., Yan, J., Goldberg, D.M., Ultrasensitive assay for three polyphenols (catechin, quercetin and resveratrol) and their conjugates in biological fluids utilizing gas chromatography with mass selective detection. J. Chromatogr. B 757:1 (2001), 161–172.
149. Soukas, A.A., Kane, E.A., Carr, C.E., Melo, J.A., Ruvkun, G., Rictor/TORC2 regulates fat metabolism, feeding, growth, and life span in Caenorhabditis elegans. Genes Dev. 23:4 (2009), 496–511.
150. Stahl, S., Branca, R.M., Efazat, G., Ruzzene, M., Zhivotovsky, B., Lewensohn, R., Viktorsson, K., Lehtio, J., Phosphoproteomic profiling of NSCLC cells reveals that ephrin B3 regulates pro-survival signaling through akt1-mediated phosphorylation of the EphA2 receptor. J. Proteome Res. 10:5 (2011), 2566–2578.
151. Stenvinkel, P., Kooman, J.P., Shiels, P.G., Nutrients and ageing: what can we learn about ageing interactions from animal biology?. Curr. Opin. Clin. Nutr. Metab. Care 19:1 (2016), 19–25.
152. Stout, M.B., Evans, G.L., Jurczak, M.J., Zhu, Y., Xu, M., Palmer, A.K., Pirtskhalava, T., White, T.A., Singh, R.J., LeBrasseur, N.K., LB-OR03-3: alleviation of age-related metabolic dysfunction by 17α-estradiol: a novel therapeutic strategy. Endocr. Rev., 36(2), 2015.
153. Suh, Y., Afaq, F., Khan, N., Johnson, J.J., Khusro, F.H., Mukhtar, H., Fisetin induces autophagic cell death through suppression of mTOR signaling pathway in prostate cancer cells. Carcinogenesis 31:8 (2010), 1424–1433.
154. Suh, K.S., Chon, S., Choi, E.M., Protective effects of honokiol against methylglyoxal-induced osteoblast damage. Chem. Biol. Interact. 244 (2016), 169–177.
155. Syed, D.N., Adhami, V.M., Khan, M.I., Mukhtar, H., Inhibition of Akt/mTOR signaling by the dietary flavonoid fisetin. Anti-Cancer Agents Med. Chem. 13:7 (2013), 995–1001.
156. Syed, D.N., Chamcheu, J.C., Khan, M.I., Sechi, M., Lall, R.K., Adhami, V.M., Mukhtar, H., Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. Biochem. Pharmacol. 89:3 (2014), 349–360.
157. Thoreen, C.C., Chantranupong, L., Keys, H.R., Wang, T., Gray, N.S., Sabatini, D.M., A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485:7396 (2012), 109–113.
158. Tunc, S.Y., Agacayak, E., Goruk, N.Y., Icen, M.S., Turgut, A., Alabalik, U., Togrul, C., Ekinci, C., Ekinci, A., Gul, T., Protective effects of honokiol on ischemia/reperfusion injury of rat ovary: an experimental study. Drug Des. Dev. Ther. 10 (2016), 1077–1083.
159. Unruhe, B., Schroder, E., Wunsch, D., Knauer, S.K., An old flame never dies: survivin in cancer and cellular senescence. Gerontology 62:2 (2016), 173–181.
160. Vicente, R., Mausset-Bonnefont, A.L., Jorgensen, C., Louis-Plence, P., Brondello, J.M., Cellular senescence impact on immune cell fate and function. Aging Cell 15:3 (2016), 400–406.
161. Vilchez, D., Saez, I., Dillin, A., The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat. Commun., 5, 2014, 5659.
162. Vissers, M.N., Zock, P.L., Katan, M.B., Bioavailability and antioxidant effects of olive oil phenols in humans: a review. Eur. J. Clin Nutr. 58:6 (2004), 955–965.
163. Wang, X.H., Duan, X.M., Yang, G.L., Zhang, X.Y., Deng, L.Y., Zheng, H., Deng, C.Y., Wen, J.L., Wang, N., Peng, C., Zhao, X., Wei, Y.Q., Chen, L.J., Honokiol crosses BBB and BCSFB, and inhibits brain tumor growth in rat 9L intracerebral gliosarcoma model and human U251 xenograft glioma model. PLoS One, 6(4), 2011, e18490.
164. Wang, S., Su, R., Nie, S., Sun, M., Zhang, J., Wu, D., Moustaid-Moussa, N., Application of nanotechnology in improving bioavailability and bioactivity of diet-derived phytochemicals. J. Nutr. Biochem. 25:4 (2014), 363–376.
165. Wang, S., Liu, X., Sun, Z., MicroRNA-150 knockout (miR150-KO) prevents age-Related glucose intolerance and extends life-span. FASEB J. 29:1 Supplement (2015), 996–999.
166. Wang, Y., Chen, B., Longtine, M.S., Nelson, D.M., Punicalagin promotes autophagy to protect primary human syncytiotrophoblasts from apoptosis. Reproduction 151:2 (2016), 97–104.
167. Wang, Y., Jiang, L.L., Wu, J.F., Liu, Z., Protective effect of Honokiol against endometriosis in rats via attenuating survivin and Bcl-2: a mechanistic study. Cell. Mol. Biol. 62:1 (2016), 1–5.
168. Warr, M.R., Binnewies, M., Flach, J., Reynaud, D., Garg, T., Malhotra, R., Debnath, J., Passegué, E., FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494:7437 (2013), 323–327.
169. Watanabe, M., Hisatake, M., Fujimori, K., Fisetin suppresses lipid accumulation in mouse adipocytic 3T3-L1Cells by repressing GLUT4-mediated glucose uptake through inhibition of mTOR-C/EBP alpha signaling. J. Agric. Food Chem. 63:20 (2015), 4979–4987.
170. Wee, L.H., Morad, N.A., Aan, G.J., Makpol, S., Ngah, W.Z.W., Yusof, Y.A.M., Mechanism of chemoprevention against colon cancer cells using combined gelam honey and ginger extract via mTOR and Wnt/β-catenin pathways. Asian Pacific J. Cancer Prev. 16:15 (2015), 6549–6556.
171. White, R.R., Milholland, B., de Bruin, A., Curran, S., Laberge, R.M., van Steeg, H., Campisi, J., Maslov, A.Y., Vijg, J., Controlled induction of DNA double-strand breaks in the mouse liver induces features of tissue ageing. Nat. Commun., 6, 2015, 6790.
172. Wrighton, K.H., Ageing: staying alive without CRTC-1. Nat. Rev. Mol. Cell Biol 12:4 (2011), 206–207.
173. Wu, X.N., Chen, X.G., Hu, Z.D., High-performance liquid simultaneous determination chromatographic method for of honokiol and magnolol in rat plasma. Talanta 59:1 (2003), 115–121.
174. Wu, M.Y., Hung, S.K., Fu, S.L., Immunosuppressive effects of fisetin in ovalbumin-induced asthma through inhibition of NF-kappaB activity. J. Agric. Food Chem. 59:19 (2011), 10496–10504.
175. Xu, L., Wang, S., Li, B., Sun, A., Zou, Y., Ge, J., A protective role of ciglitazone in ox‐LDL‐induced rat microvascular endothelial cells via modulating PPAR γ‐dependent AMPK/eNOS pathway. J. Cell. Mol. Med. 19:1 (2015), 92–102.
176. Yang, H., Rudge, D.G., Koos, J.D., Vaidialingam, B., Yang, H.J., Pavletich, N.P., mTOR kinase structure, mechanism and regulation. Nature 497:7448 (2013), 217–223.
177. Yao, K., Zhang, L., Zhang, Y., Ye, P., Zhu, N., The flavonoid, fisetin, inhibits UV radiation-induced oxidative stress and the activation of NF-kappaB and MAPK signaling in human lens epithelial cells. Mol. Vis. 14 (2008), 1865–1871.
178. Yeh, P.S., Wang, W., Chang, Y.A., Lin, C.J., Wang, J.J., Chen, R.M., Honokiol induces autophagy of neuroblastoma cells through activating the PI3K/Akt/mTOR and endoplasmic reticular stress/ERK1/2 signaling pathways and suppressing cell migration. Cancer Lett. 370:1 (2016), 66–77.
179. Yeh, C.K., Cellular senescence and aging. Oral Dis., 2016, 10.1111/odi.12483.
180. Yu, Y.W., Li, M.X., Su, N., Zhang, Z.Y., Zhao, H.D., Yu, H., Xu, Y.L., Honokiol protects against renal ischemia/reperfusion injury via the suppression of oxidative stress, iNOS, inflammation and STAT3 in rats. Mol. Med. Rep. 13:2 (2016), 1353–1360.
181. Yuan, Z.P., Chen, L.J., Fan, L.Y., Tang, M.H., Yang, G.L., Yang, H.S., Du, X.B., Wang, G.Q., Yao, W.X., Zhao, Q.M., Ye, B., Wang, R., Diao, P., Zhang, W., Wu, H.B., Zhao, X., Wei, Y.Q., Liposomal quercetin efficiently suppresses growth of solid tumors in murine models. Clin. Cancer Res. 12:10 (2006), 3193–3199.
182. Zhang, Y., Nicholatos, J., Dreier, J.R., Ricoult, S.J., Widenmaier, S.B., Hotamisligil, G.S., Kwiatkowski, D.J., Manning, B.D., Coordinated regulation of protein synthesis and degradation by mTORC1. Nature 513:7518 (2014), 440–443.
183. Zhang, L., Shamaladevi, N., Jayaprakasha, G., Patil, B., Lokeshwar, B., Polyphenol-rich extract of Pimenta dioica berries (Allspice) kills breast cancer cells by autophagy and delays growth of triple negative breast cancer in athymic mice. Oncotarget 6:18 (2015), 16379–16395.
184. Zhang, Y., Biology of the Mi-2/NuRD complex in SLAC (stemness, longevity/ageing, and cancer). Gene Regul. Syst. Biol. 5 (2011), 1–26.
185. Zhang, Y., Ageing and cancer: breaking the don't put all eggs in one basket and natural self-organisation, and their potential reprogramming via modulation of mi-2/NuRD, mTOR kinase and metabolism. Enz. Eng., 2, 2012, 109.
186. Zhao, G.M., Han, X.D., Zheng, S.W., Li, Z., Sha, Y., Ni, J., Sun, Z., Qiao, S., Song, Z.Q., Curcumin induces autophagy, inhibits proliferation and invasion by downregulating AKT/mTOR signaling pathway in human melanoma cells. Oncol. Rep. 35:2 (2016), 1065–1074.
187. Zhou, C.H., Wang, C.X., Xie, G.B., Wu, L.Y., Wei, Y.X., Wang, Q., Zhang, H.S., Hang, C.H., Zhou, M.L., Shi, J.X., Fisetin alleviates early brain injury following experimental subarachnoid hemorrhage in rats possibly by suppressing TLR 4/NF-kappaB signaling pathway. Brain Res. 1629 (2015), 250–259.
188. Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A.C., Ding, H., Giorgadze, N., Palmer, A.K., Ikeno, Y., Hubbard, G.B., Lenburg, M., O'Hara, S.P., LaRusso, N.F., Miller, J.D., Roos, C.M., Verzosa, G.C., LeBrasseur, N.K., Wren, J.D., Farr, J.N., Khosla, S., Stout, M.B., McGowan, S.J., Fuhrmann-Stroissnigg, H., Gurkar, A.U., Zhao, J., Colangelo, D., Dorronsoro, A., Ling, Y.Y., Barghouthy, A.S., Navarro, D.C., Sano, T., Robbins, P.D., Niedernhofer, L.J., Kirkland, J.L., The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14:4 (2015), 644–658.
189. Zoncu, R., Efeyan, A., Sabatini, D.M., mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12:1 (2011), 21–35.
190. de Bock, M., Thorstensen, E.B., Derraik, J.G.B., Henderson, H.V., Hofman, P.L., Cutfield, W.S., Human absorption and metabolism of oleuropein and hydroxytyrosol ingested as olive (Olea europaea L.) leaf extract. Mol. Nutr. Food Res. 57:11 (2013), 2079–2085.
191. de Lange, P., Cioffi, F., Silvestri, E., Moreno, M., Goglia, F., Lanni, A., (Healthy) ageing: focus on iodothyronines. Int. J. Mol. Sci. 14:7 (2013), 13873–13892.
192. de Oliveira, M.R., Nabavi, S.M., Braidy, N., Setzer, W.N., Ahmed, T., Nabavi, S.F., Quercetin and the mitochondria: a mechanistic view. Biotechnol. Adv., 2015, 10.1016/j.biotechadv.2015.12.014.