Volume 10 Issue 6
Jun.  2019
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Lingling Geng, Zunpeng Liu, Weiqi Zhang, Wei Li, Zeming Wu, Wei Wang, Ruotong Ren, Yao Su, Peichang Wang, Liang Sun, Zhenyu Ju, Piu Chan, Moshi Song, Jing Qu, Guang-Hui Liu. Chemical screen identifies a geroprotective role of quercetin in premature aging[J]. Protein&Cell, 2019, 10(6): 417-435. doi: 10.1007/s13238-018-0567-y
Citation: Lingling Geng, Zunpeng Liu, Weiqi Zhang, Wei Li, Zeming Wu, Wei Wang, Ruotong Ren, Yao Su, Peichang Wang, Liang Sun, Zhenyu Ju, Piu Chan, Moshi Song, Jing Qu, Guang-Hui Liu. Chemical screen identifies a geroprotective role of quercetin in premature aging[J]. Protein&Cell, 2019, 10(6): 417-435. doi: 10.1007/s13238-018-0567-y

Chemical screen identifies a geroprotective role of quercetin in premature aging

doi: 10.1007/s13238-018-0567-y
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This work was supported by the National Key Research and Development Program of China (2017YFA0103304), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010100), the National Key Research and Development Program of China (2015CB964800, 2017YFA0102802, 2014CB910503 and 2018YFA0107203), the National High Technology Research and Development Program of China (2015AA020307), the National Natural Science Foundation of China (Grant Nos. 31671429, 91749202, 91749123, 81625009, 81330008, 81371342, 81471414, 81422017, 81601233, 81671377, 31601109, 31601158, 81771515 and 81701388), Program of Beijing Municipal Science and Technology Commission (Z151100003 915072), Key Research Program of the Chinese Academy of Sciences (KJZDEW-TZ-L05), Beijing Municipal Commission of Health and Family Planning (PXM2018_026283_000002), and Advanced Innovation Center for Human Brain Protection (117212).

  • Received Date: 2018-03-12
  • Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.
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  • [1]
    Anders S, Pyl PT, Huber W (2015) HTSeq-a Python framework to work with high-throughput sequencing data. Bioinformatics 31:166-169
    [2]
    Ansgar B (2013) Inhibition of mTOR Signaling by Quercetin in Cancer Treatment and Prevention. Anticancer Agents Med Chem 13:1025-1031
    [3]
    Bahar E, Kim J-Y, Yoon H (2017) Quercetin Attenuates ManganeseInduced Neuroinflammation by Alleviating Oxidative Stress through Regulation of Apoptosis, iNOS/NF-κB and HO-1/Nrf2 Pathways. Int J Mol Sci 18:1989
    [4]
    Benayoun BA, Pollina EA, Brunet A (2015) Epigenetic regulation of ageing:linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16:593-610
    [5]
    Burtner CR, Kennedy BK (2010) Progeria syndromes and ageing:what is the connection? Nature Reviews Molecular Cell Biology 11:567
    [6]
    Campisi J (2013) Aging, Cellular Senescence, and Cancer. Annual review of physiology 75:685-705
    [7]
    Chang J, Wang Y, Shao L, Laberge R-M, Demaria M, Campisi J, Janakiraman K, Sharpless NE, Ding S, Feng W et al (2016) Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nature medicine 22:78-83
    [8]
    Chen J, Bardes EE, Aronow BJ, Jegga AG (2009) ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucl Acids Res 37:W305-W311
    [9]
    Chiow KH, Phoon MC, Putti T, Tan BKH, Chow VT (2016) Evaluation of antiviral activities of Houttuynia cordata Thunb. extract, quercetin, quercetrin and cinanserin on murine coronavirus and dengue virus infection. Asian Pacific Journal of Tropical Medicine 9:1-7
    [10]
    Chondrogianni N, Kapeta S, Chinou I, Vassilatou K, Papassideri I, Gonos ES (2010) Anti-ageing and rejuvenating effects of quercetin. Experimental Gerontology 45:763-771
    [11]
    Dai Y, Zhang H, Zhang J, Yan M (2018) Isoquercetin attenuates oxidative stress and neuronal apoptosis after ischemia/reperfusion injury via Nrf2-mediated inhibition of the NOX4/ROS/NFkappaB pathway. Chem Biol Interact 284:32-40
    [12]
    Darband Saber G, Kaviani M, Yousefi B, Sadighparvar S, Pakdel Firouz G, Attari Javad A, Mohebbi I, Naderi S, Majidinia M (2018) Quercetin:A functional dietary flavonoid with potential chemopreventive properties in colorectal cancer. Journal of Cellular Physiology 233:6544-6560
    [13]
    Debacq-Chainiaux F, Erusalimsky JD, Campisi J, Toussaint O (2009) Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc 4:1798-1806
    [14]
    Duan S, Yuan G, Liu X, Ren R, Li J, Zhang W, Wu J, Xu X, Fu L, Li Y (2015) PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype. Nature Communications 6:10068
    [15]
    Fang J, Yang J, Wu X, Zhang G, Li T, Wang X, Zhang H, Wang C, Liu G-H, Wang L (2018) Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell 17(4):e12765
    [16]
    Fu L, Xu X, Ren R, Wu J, Zhang W, Yang J, Ren X, Wang S, Zhao Y, Sun L et al (2016) Modeling xeroderma pigmentosum associated neurological pathologies with patients-derived iPSCs. Protein & Cell 7:210-221
    [17]
    Gao W, Pu L, Chen M, Wei J, Xin Z, Wang Y, Yao Z, Shi T, Guo C (2018) Glutathione homeostasis is significantly altered by quercetin via the Keap1/Nrf2 and MAPK signaling pathways in rats. Journal of Clinical Biochemistry and Nutrition 62:56-62
    [18]
    Griffiths K, Aggarwal BB, Singh RB, Buttar HS, Wilson D, De Meester F (2016) Food Antioxidants and Their Anti-Inflammatory Properties:A Potential Role in Cardiovascular Diseases and Cancer Prevention. Diseases 4:28
    [19]
    Harhouri K, Frankel D, Bartoli C, Roll P, De Sandre-Giovannoli A, Lévy N (2018) An overview of treatment strategies for Hutchinson-Gilford Progeria Syndrome. Nucleus 9(1):246-257
    [20]
    Harley CB (1991) Telomere loss:mitotic clock or genetic time bomb? Mutation Research 256:271-282
    [21]
    Hennekam Raoul CM (2006) Hutchinson-Gilford progeria syndrome:Review of the phenotype. American Journal of Medical Genetics Part A 140A:2603-2624
    [22]
    Kampkötter A, Timpel C, Zurawski RF, Ruhl S, Chovolou Y, Proksch P, Wätjen W (2008) Increase of stress resistance and lifespan of Caenorhabditis elegans by quercetin. Comparative Biochemistry and Physiology Part B:Biochemistry and Molecular Biology 149:314-323
    [23]
    Kim D, Langmead B, Salzberg SL (2015) HISAT:a fast spliced aligner with low memory requirements. Nature methods 12:357-360
    [24]
    Kim Y, Kim CS, Joe Y, Chung HT, Ha TY, Yu R (2018) Quercetin Reduces Tumor Necrosis Factor Alpha-Induced Muscle Atrophy by Upregulation of Heme Oxygenase-1. Journal of medicinal food 21:551-559
    [25]
    Kreienkamp R, Croke M, Neumann MA, Bedia-Diaz G, Graziano S, Dusso A, Dorsett D, Carlberg C, Gonzalo S (2016) Vitamin D receptor signaling improves Hutchinson-Gilford progeria syndrome cellular phenotypes. Oncotarget 7:30018-30031
    [26]
    Kubben N, Zhang W, Wang L, Voss TC, Yang J, Qu J, Liu GH, Misteli T (2016) Repression of the antioxidant NRF2 pathway in premature aging. Cell 165(6):1361-1374
    [27]
    Kudlow BA, Kennedy BK, Monnat RJ Jr (2007) Werner and Hutchinson-Gilford progeria syndromes:mechanistic basis of human progeroid diseases. Nature Reviews Molecular Cell Biology 8:394
    [28]
    López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The Hallmarks of Aging. Cell 153:1194-1217
    [29]
    Labbé A, Turaga RV, Paquet ER, Garand C, Lebel M (2010) Expression profiling of mouse embryonic fibroblasts with a deletion in the helicase domain of the Werner Syndrome gene homologue treated with hydrogen peroxide. Bmc Genomics 11:127
    [30]
    Lebel M (2001) Werner syndrome:genetic and molecular basis of a premature aging disorder. Cellular and molecular life sciences:CMLS 58:857-867
    [31]
    Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S, Liu H, Yin Y (2016a) Quercetin. Inflammation and Immunity. Nutrients 8:167
    [32]
    Li Y, Zhang W, Chang L, Han Y, Sun L, Gong X, Tang H, Liu Z, Deng H, Ye Y et al (2016b) Vitamin C alleviates aging defects in a stem cell model for Werner syndrome. Protein & Cell 7:478-488
    [33]
    Liu GH, Barkho BZ, Ruiz S, Diep D, Qu J, Yang S-L, Panopoulos AD, Suzuki K, Kurian L, Walsh C et al (2011a) Recapitulation of premature aging with iPSCs from Hutchinson-Gilford progeria syndrome. Nature 472:221-225
    [34]
    Liu GH, Suzuki K, Qu J, Sancho-Martinez I, Yi F, Li M, Kumar S, Nivet E, Kim J, Soligalla RD et al (2011b) Targeted Gene Correction of Laminopathy-Associated LMNA Mutations in Patient-Specific iPSCs. Cell stem cell 8:688-694
    [35]
    Liu W, Zhang M, Feng J, Fan A, Zhou Y, Xu Y (2017) The Influence of Quercetin on Maternal Immunity, Oxidative Stress, and Inflammation in Mice with Exposure of Fine Particulate Matter during Gestation. International Journal of Environmental Research and Public Health 14:592
    [36]
    Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW (2005) DNA Repair, Genome Stability, and Aging. Cell 120:497-512
    [37]
    Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome biology 15:550
    [38]
    Murfuni I, Santis AD, Federico M, Bignami M, Pichierri P, Franchitto A (2012) Perturbed replication induced genome wide or at common fragile sites is differently managed in the absence of WRN. Carcinogenesis 33:1655
    [39]
    Ogrodnik M, Miwa S, Tchkonia T, Tiniakos D, Wilson CL, Lahat A, Day CP, Burt A, Palmer A, Anstee QM et al (2017) Cellular senescence drives age-dependent hepatic steatosis. Nature Communications 8:15691
    [40]
    Opresko PL, Cheng WH, von Kobbe C, Harrigan JA, Bohr VA (2003) Werner syndrome and the function of the Werner protein; what they can teach us about the molecular aging process. Carcinogenesis 24:791-802
    [41]
    Ozgenc A, Loeb LA (2006) Werner Syndrome, aging and cancer. Genome dynamics 1:206-217
    [42]
    Pan H, Guan D, Liu X, Li J, Wang L, Wu J, Zhou J, Zhang W, Ren R, Zhang W (2016) SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2. Cell Research 26:190-205
    [43]
    Polosak J, Kurylowicz A, Roszkowska-Gancarz M, Owczarz M, Puzianowska-Kuznicka M (2011) Aging is accompanied by a progressive decrease of expression of the WRN gene in human blood mononuclear cells. Journals of Gerontology 66:19
    [44]
    Ren R, Deng L, Xue Y, Suzuki K, Zhang W, Yu Y, Wu J, Sun L, Gong X, Luan H (2017a) Visualization of aging-associated chromatin alterations with an engineered TALE system. Cell Research 27:483-504
    [45]
    Ren R, Ocampo A, Liu GH, Izpisua Belmonte JC (2017b) Regulation of Stem Cell Aging by Metabolism and Epigenetics. Cell metabolism 26:460-474
    [46]
    Ren X, Lim S, Ji Z, Yuh J, Peng V, Smith MT, Zhang L (2011) Comparison of Proliferation and Genomic Instability Responses to WRN Silencing in Hematopoietic HL60 and TK6 Cells. Plos One 6:e14546
    [47]
    Reszka E, Wieczorek E, Jablonska E, Janasik B, Fendler W, Wasowicz W (2015) Association between plasma selenium level and NRF2 target genes expression in humans. Journal of Trace Elements in Medicine and Biology 30:102-106
    [48]
    Salvatore C (2010) The Role of Quercetin, Flavonols and Flavones in Modulating Inflammatory Cell Function. Inflammation & Allergy-Drug Targets (Discontinued) 9:263-285
    [49]
    Seki M, Otsuki M, Ishii Y, Tada S, Enomoto T (2008) RecQ family helicases in genome stability:lessons from gene disruption studies in DT40 cells. Cell Cycle 7:2472-2478
    [50]
    Shamanna RA, Croteau DL, Lee JH, Bohr VA (2017) Recent advances in understanding werner syndrome. F1000research 6:1779
    [51]
    Smith JR, Pereirasmith OM (1996) Replicative Senescence:Implications for in Vivo Aging and Tumor Suppression. Science 273:63-67
    [52]
    Sohn E-J, Kim JM, Kang S-H, Kwon J, An HJ, Sung J-S, Cho KA, Jang I-S, Choi J-S (2018) Restoring effects of natural anti-oxidant quercetin on cellular senescent human dermal fibroblasts. Am J Chin Med 46(4):1-21
    [53]
    Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P et al (2017) The STRING database in 2017:quality-controlled protein-protein association networks, made broadly accessible. Nucl Acids Res 45:D362-D368
    [54]
    Tacutu R, Craig T, Budovsky A, Wuttke D, Lehmann G, Taranukha D, Costa J, Fraifeld VE, de Magalhaes JP (2013) Human Ageing Genomic Resources:integrated databases and tools for the biology and genetics of ageing. Nucleic Acids Res 41:D1027-1033
    [55]
    Uccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nature reviews Immunology 8:726-736
    [56]
    Ullrich N, Gordon L (2015) Chapter 18-Hutchinson-Gilford progeria syndrome. In:Islam MP, Roach ES (eds) Neurocutaneous Syndromes. Handbook of Clinical Neurology, vol 132. Elsevier, pp 249-264
    [57]
    Villeponteau B (1997) The heterochromatin loss model of aging. Experimental Gerontology 32:383-394
    [58]
    Wang P, Liu Z, Zhang X, Li J, Sun L, Ju Z, Li J, Chan P, Liu G-H, Zhang W et al (2018a) CRISPR/Cas9-mediated gene knockout reveals a guardian role of NF-κB/RelA in maintaining the homeostasis of human vascular cells. Protein Cell. https://doi.org/10.1007/s13238-018-0560-5
    [59]
    Wang S, Hu B, Ding Z, Dang Y, Wu J, Li D, Liu X, Xiao B, Zhang W, Ren R et al (2018b) ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells. Cell Discovery 4:2
    [60]
    Wu Z, Zhang W, Song M, Wang W, Wei G, Li W, Lei J, Huang Y, Sang Y, Chan P et al (2018) Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome.Protein & Cell 9:333-350
    [61]
    Xu Z, Feng W, Shen Q, Yu N, Yu K, Wang S, Chen Z, Shioda S, Guo Y (2017) Rhizoma Coptidis and Berberine as a Natural Drug to Combat Aging and Aging-Related Diseases via Anti-Oxidation and AMPK Activation. Aging and Disease 8:760-777
    [62]
    Yang J, Cai N, Yi F, Liu GH, Qu J, Izpisua Belmonte JC (2014) Gating pluripotency via nuclear pores. Trends in molecular medicine 20:1-7
    [63]
    Yang J, Li J, Suzuki K, Liu X, Wu J, Zhang W, Ren R, Zhang W, Chan P, Izpisua Belmonte JC et al (2017) Genetic enhancement in cultured human adult stem cells conferred by a single nucleotide recoding. Cell Res 27:1178-1181
    [64]
    Yu CE, Oshima J, Fu YH, Wijsman EM, Hisama F, Alisch R, Matthews S, Nakura J, Miki T, Ouais S (1996) Positional cloning of the Werner's syndrome gene. Science 272:258-262
    [65]
    Yu QC, Song W, Wang D, Zeng YA (2016) Identification of blood vascular endothelial stem cells by the expression of protein C receptor. Cell Research 26:1079-1098
    [66]
    Zhang W, Li J, Suzuki K, Qu J, Wang P, Zhou J, Liu X, Ren R, Xu X, Ocampo A et al (2015) A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science (New York, NY) 348:1160-1163
    [67]
    Zhou M, Wang S, Zhao A, Wang K, Fan Z, Yang H, Liao W, Bao S, Zhao L, Zhang Y et al (2012) Transcriptomic and Metabonomic Profiling Reveal Synergistic Effects of Quercetin and Resveratrol Supplementation in High Fat Diet Fed Mice. Journal of Proteome Research 11:4961-4971
    [68]
    Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, Palmer AK, Ikeno Y, Hubbard GB, Lenburg M et al (2015) The Achilles' heel of senescent cells:from transcriptome to senolytic drugs. Aging Cell 14:644-658
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