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

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
    Ansgar B (2013) Inhibition of mTOR Signaling by Quercetin in Cancer Treatment and Prevention. Anticancer Agents Med Chem 13:1025-1031
    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
    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
    Burtner CR, Kennedy BK (2010) Progeria syndromes and ageing:what is the connection? Nature Reviews Molecular Cell Biology 11:567
    Campisi J (2013) Aging, Cellular Senescence, and Cancer. Annual review of physiology 75:685-705
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    Harley CB (1991) Telomere loss:mitotic clock or genetic time bomb? Mutation Research 256:271-282
    Hennekam Raoul CM (2006) Hutchinson-Gilford progeria syndrome:Review of the phenotype. American Journal of Medical Genetics Part A 140A:2603-2624
    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
    Kim D, Langmead B, Salzberg SL (2015) HISAT:a fast spliced aligner with low memory requirements. Nature methods 12:357-360
    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
    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
    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
    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
    López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The Hallmarks of Aging. Cell 153:1194-1217
    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
    Lebel M (2001) Werner syndrome:genetic and molecular basis of a premature aging disorder. Cellular and molecular life sciences:CMLS 58:857-867
    Li Y, Yao J, Han C, Yang J, Chaudhry MT, Wang S, Liu H, Yin Y (2016a) Quercetin. Inflammation and Immunity. Nutrients 8:167
    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
    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
    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
    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
    Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt FW (2005) DNA Repair, Genome Stability, and Aging. Cell 120:497-512
    Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome biology 15:550
    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
    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
    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
    Ozgenc A, Loeb LA (2006) Werner Syndrome, aging and cancer. Genome dynamics 1:206-217
    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
    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
    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
    Ren R, Ocampo A, Liu GH, Izpisua Belmonte JC (2017b) Regulation of Stem Cell Aging by Metabolism and Epigenetics. Cell metabolism 26:460-474
    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
    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
    Salvatore C (2010) The Role of Quercetin, Flavonols and Flavones in Modulating Inflammatory Cell Function. Inflammation & Allergy-Drug Targets (Discontinued) 9:263-285
    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
    Shamanna RA, Croteau DL, Lee JH, Bohr VA (2017) Recent advances in understanding werner syndrome. F1000research 6:1779
    Smith JR, Pereirasmith OM (1996) Replicative Senescence:Implications for in Vivo Aging and Tumor Suppression. Science 273:63-67
    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
    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
    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
    Uccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nature reviews Immunology 8:726-736
    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
    Villeponteau B (1997) The heterochromatin loss model of aging. Experimental Gerontology 32:383-394
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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
    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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