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Human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases

Abstract

A key goal of geroscience research is to identify effective interventions to extend human healthspan, the years of healthy life. Currently, majority of the geroprotectors are found by screening compounds in model organisms; whether they will be effective in humans is largely unknown. Here we present a new strategy called ANDRU (aging network based drug discovery) to help the discovery of human geroprotectors. It first identifies human aging subnetworks that putatively function at the interface between aging and age-related diseases; it then screens for pharmacological interventions that may “reverse” the age-associated transcriptional changes occurred in these subnetworks. We applied ANDRU to human adipose gene expression data from the Genotype Tissue Expression (GTEx) project. For the top 31 identified compounds, 19 of them showed at least some evidence supporting their function in improving metabolic traits or lifespan, which include type 2 diabetes drugs such as pioglitazone. As the query aging genes were refined to the ones with more intimate links to diseases, ANDRU identified more meaningful drug hits than the general approach without considering the underlying network structures. In summary, ANDRU represents a promising human data-driven strategy that may speed up the discovery of interventions to extend human healthspan.

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References

  • Addae JI, Rothwell NJ, Stock MJ, Stone TW (1986) Activation of thermogenesis of brown fat in rats by baclofen. Neuropharmacology 25:627–631

    CAS  PubMed  Article  Google Scholar 

  • Afkhami-Ardekani M, Shojaoddiny-Ardekani A (2007) Effect of vitamin C on blood glucose, serum lipids & serum insulin in type 2 diabetes patients. Indian J Med Res 126:471–474

    CAS  PubMed  Google Scholar 

  • Aliper A, Belikov AV, Garazha A, Jellen L, Artemov A, Suntsova M, Ivanova A, Venkova L, Borisov N, Buzdin A, Mamoshina P, Putin E, Swick AG, Moskalev A, Zhavoronkov A (2016) In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state. Aging 8:2127–2152

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Anders S, Huber W (2010) Differential expression analysis for sequence count data. Genome Biol 11:R106

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Arima H, Oiso Y (2010) Positive effect of baclofen on body weight reduction in obese subjects: a pilot study. Intern Med 49:2043–2047

    CAS  PubMed  Article  Google Scholar 

  • Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J et al (2016) Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530:184–189

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Bala K, Tripathy BC, Sharma D (2006) Neuroprotective and anti-ageing effects of curcumin in aged rat brain regions. Biogerontology 7:81–89

    CAS  PubMed  Article  Google Scholar 

  • Barardo D, Thornton D, Thoppil H, Walsh M, Sharifi S, Ferreira S, Anžič A, Fernandes M, Monteiro P, Grum T, Cordeiro R, de-Souza EA, Budovsky A, Araujo N, Gruber J, Petrascheck M, Fraifeld VE, Zhavoronkov A, Moskalev A, de Magalhães JP (2017) The DrugAge database of aging-related drugs. Aging Cell 16:594–597

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Blankson H, Stakkestad JA, Fagertun H, Thom E, Wadstein J, Gudmundsen O (2000) Conjugated linoleic acid reduces body fat mass in overweight and obese humans. J Nutr 130:2943–2948

    CAS  PubMed  Article  Google Scholar 

  • Bogacka I, Ukropcova B, McNeil M, Gimble JM, Smith SR (2005) Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro. J Clin Endocrinol Metab 90:6650–6656

    CAS  PubMed  Article  Google Scholar 

  • Brandstadt S, Schmeisser K, Zarse K, Ristow M (2013) Lipid-lowering fibrates extend C. elegans lifespan in a NHR-49/PPARalpha-dependent manner. Aging (Albany NY) 5:270–275

    Article  Google Scholar 

  • Calkin AC, Tontonoz P (2012) Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol 13:213–224

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Calvert S, Tacutu R, Sharifi S, Teixeira R, Ghosh P, Magalhães J (2016) A network pharmacology approach reveals new candidate caloric restriction mimetics in C. elegans. Aging Cell 15:256–266

    CAS  PubMed  Article  Google Scholar 

  • Chen N, Wang J (2018) Wnt/β-catenin signaling and obesity. Front Physiol 9:792–792

    PubMed  PubMed Central  Article  Google Scholar 

  • Chen EY, Tan CM, Kou Y, Duan Q, Wang Z, Meirelles GV, Clark NR, Ma’ayan A (2013) Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics 14:128

    PubMed  PubMed Central  Article  Google Scholar 

  • Choi S, Youn J, Kim K, Joo DH, Shin S, Lee J, Lee HK, An IS, Kwon S, Youn HJ, Ahn KJ, An S, Cha HJ (2016) Apigenin inhibits UVA-induced cytotoxicity in vitro and prevents signs of skin aging in vivo. Int J Mol Med 38:627–634

    CAS  PubMed  Article  Google Scholar 

  • Csermely P, Korcsmáros T, Kiss H, London G, Nussinov R (2013) Structure and dynamics of molecular networks: a novel paradigm of drug discovery a comprehensive review. Pharmacol Ther 138:333–408

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Dakhale GN, Chaudhari HV, Shrivastava M (2011) Supplementation of vitamin C reduces blood glucose and improves glycosylated hemoglobin in type 2 diabetes mellitus: a randomized, double-blind study. Adv Pharmacol Sci 2011:5

    Google Scholar 

  • Donertas HM, Fuentealba Valenzuela M, Partridge L, Thornton JM (2018) Gene expression-based drug repurposing to target aging. Aging Cell 17:e12819

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Duan Q, Reid SP, Clark NR, Wang Z, Fernandez NF, Rouillard AD, Readhead B, Tritsch SR, Hodos R, Hafner M, Niepel M, Sorger PK, Dudley JT, Bavari S, Panchal RG, Ma’ayan A (2016) L1000CDS(2): LINCS L1000 characteristic direction signatures search engine. NPJ Syst Biol Appl 2:16015

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Dudley JT, Sirota M, Shenoy M, Pai RK, Roedder S, Chiang AP, Morgan AA, Sarwal MM, Pasricha PJ, Butte AJ (2011) Computational repositioning of the anticonvulsant Topiramate for inflammatory bowel disease. Sci Transl Med 3:96ra76

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Escande C, Nin V, Price NL, Capellini V, Gomes AP, Barbosa MT, O'Neil L, White TA, Sinclair DA, Chini EN (2013) Flavonoid Apigenin is an inhibitor of the NAD(+)ase CD38 implications for cellular NAD(+) metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes 62:1084–1093

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Everitt AV, Hilmer SN, Brand-Miller JC, Jamieson HA, Truswell AS, Sharma AP, Mason RS, Morris BJ, Couteur DGL (2006) Dietary approaches that delay age-related diseases. Clin Interv Aging 1:11–31

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Fang MZ, Chen DP, Yang CS (2007) Dietary polyphenols may affect DNA methylation. J Nutr 137:223s–228s

    CAS  PubMed  Article  Google Scholar 

  • Farbood Y, Ghaderi S, Rashno M, Khoshnam SE, Khorsandi L, Sarkaki A (2019) Sesamin: a promising protective agent against diabetes-associated cognitive decline in rats. Life Sci 230:169–177

    CAS  PubMed  Article  Google Scholar 

  • Fernandes M, Wan C, Tacutu R, Barardo D, Rajput A, Wang JW, Thoppil H, Thornton D, Yang C, Freitas A, de Magalhães JP (2016) Systematic analysis of the gerontome reveals links between aging and age-related diseasesSystematic analysis of the gerontome reveals links between aging and age-related diseases. Hum Mol Genet 25:4804–4818

    CAS  PubMed  PubMed Central  Google Scholar 

  • Foster T, Kyritsopoulos C, Kumar A (2017) Central role for NMDA receptors in redox mediated impairment of synaptic function during aging and Alzheimer's disease. Behav Brain Res 322:223–232

    CAS  PubMed  Article  Google Scholar 

  • Freise C, Trowitzsch-Kienast W, Erben U, Seehofer D, Kim KY, Zeitz M, Ruehl M, Somasundaram R (2013) (+)-Episesamin inhibits adipogenesis and exerts anti-inflammatory effects in 3T3-L1 (pre)adipocytes by sustained Wnt signaling, down-regulation of PPARγ and induction of iNOS. J Nutr Biochem 24:550–555

    CAS  PubMed  Article  Google Scholar 

  • Glass D, Viñuela A, Davies MN, Ramasamy A, Parts L, Knowles D et al (2013) Gene expression changes with age in skin, adipose tissue, blood and brain. Genome Biol 14:1–12

    Article  CAS  Google Scholar 

  • Han Y, Xu G, Du H, Hu J, Liu Z, Li H et al (2017) Natural variations in stearoyl-acp desaturase genes affect the conversion of stearic to oleic acid in maize kernel. Theor Appl Genet 130:151–161

    CAS  PubMed  Article  Google Scholar 

  • Iorio F, Bosotti R, Scacheri E, Belcastro V, Mithbaokar P, Ferriero R et al (2010) Discovery of drug mode of action and drug repositioning from transcriptional responses. Proc Natl Acad Sci 107:14621–14626

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Jafari M, Khodayari B, Felgner J, Bussel II, Rose MR, Mueller LD (2007) Pioglitazone: an anti-diabetic compound with anti-aging properties. Biogerontology 8:639–651

    CAS  PubMed  Article  Google Scholar 

  • Jia R, Oda S, Tsuneyama K, Urano Y, Yokoi T (2019). Establishment of a mouse model of troglitazone-induced liver injury and analysis of its hepatotoxic mechanism. J Appl Toxicol

  • Johnson SC, Dong X, Vijg J, Suh Y (2015) Genetic evidence for common pathways in human age-related diseases. Aging Cell 14:809–817

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Johnson SC, Gonzalez B, Zhang Q, Milholland B, Zhang Z, Suh Y (2016) Network analysis of mitonuclear GWAS reveals functional networks and tissue expression profiles of disease-associated genes. Hum Genet 136:55–65

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, Franceschi C, Lithgow GJ, Morimoto RI, Pessin JE, Rando TA, Richardson A, Schadt EE, Wyss-Coray T, Sierra F (2014) Geroscience: linking aging to chronic disease. Cell 159:709–713

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Klueh U, Kaur M, Montrose DC, Kreutzer DL (2007) Inflammation and glucose sensors: use of dexamethasone to extend glucose sensor function and life span in vivo. J Diabetes Sci Technol 1:496–504

    PubMed  PubMed Central  Article  Google Scholar 

  • Knowler WC, Hamman RF, Edelstein SL, Barrett-Connor E, Ehrmann DA, Walker EA, Fowler SE, Nathan DM, Kahn SE, Diabetes Prevention Program Research Group (2005) Prevention of type 2 diabetes with troglitazone in the diabetes prevention program. Diabetes 54:1150–1156

    PubMed  Article  Google Scholar 

  • Ku HH, Brunk UT, Sohal RS (1993) Relationship between mitochondrial superoxide and hydrogen peroxide production and longevity of mammalian species. Free Radic Biol Med 15:621–627

    CAS  PubMed  Article  Google Scholar 

  • Kumar S, Lombard DB (2016) Finding Ponce de Leon’s Pill: Challenges in Screening for Anti-Aging Molecules. F1000Research 5:406

    Article  Google Scholar 

  • Kushiro M, Masaoka T, Hageshita S, Takahashi Y, Ide T, Sugano M (2002) Comparative effect of sesamin and episesamin on the activity and gene expression of enzymes in fatty acid oxidation and synthesis in rat liver. J Nutr Biochem 13:289–295

    CAS  PubMed  Article  Google Scholar 

  • Lamb J (2007) Innovation - the connectivity map: a new tool for biomedical research. Nat Rev Cancer 7:54–60

    CAS  PubMed  Article  Google Scholar 

  • Law CW, Chen Y, Shi W, Smyth GK (2014) Voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol 15:R29

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Lazarenko OP, Rzonca SO, Hogue WR, Swain FL, Suva LJ, Lecka-Czernik B (2007) Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology 148:2669–2680

    CAS  PubMed  Article  Google Scholar 

  • Le TD, Nakahara Y, Ueda M, Okumura K, Hirai J, Sato Y et al (2019) Sesamin suppresses aging phenotypes in adult muscular and nervous systems and intestines in a Drosophila senescence-accelerated model. Eur Rev Med Pharmacol Sci 23:1826–1839

    CAS  PubMed  Google Scholar 

  • Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD (2012) The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics 28:882–883

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Magnusson KR, Brim BL, Das SR (2010) Selective vulnerabilities of N-methyl-D-aspartate (NMDA) receptors during brain aging. Front Aging Neurosci 2:11

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martin LF, Richardson LS, da Silva MG, Sheller-Miller S, Menon R (2019) Dexamethasone induces primary amnion epithelial cell senescence through telomere-P21 associated pathwaydagger. Biol Reprod 100:1605–1616

    PubMed  PubMed Central  Article  Google Scholar 

  • McKenzie AT, Katsyv I, Song WM, Wang MH, Zhang B (2016) DGCA: a comprehensive R package for differential gene correlation analysis. BMC Syst Biol 10:106

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Millar JS, Ikewaki K, Bloedon LT, Wolfe ML, Szapary PO, Rader DJ (2011) Effect of rosiglitazone on HDL metabolism in subjects with metabolic syndrome and low HDL. J Lipid Res 52:136–142

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Mirza N, Sills GJ, Pirmohamed M, Marson AG (2017) Identifying New Antiepileptic Drugs Through Genomics-Based Drug Repurposing. Hum Mol Genet 26:527–537

    CAS  PubMed  Article  Google Scholar 

  • Moskalev A, Chernyagina E, de Magalhães J, Barardo D, Thoppil H, Shaposhnikov M et al (2015) Geroprotectors.org: a new, structured and curated database of current therapeutic interventions in aging and age-related disease. Aging (Albany NY) 7:616

    CAS  Article  Google Scholar 

  • Palmer AK, Kirkland JL (2016) Aging and adipose tissue: potential interventions for diabetes and regenerative medicine. Exp Gerontol 86:97–105

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Pariza MW (2004) Perspective on the safety and effectiveness of conjugated linoleic acid. Am J Clin Nutr 79:1132S–1136S

    CAS  PubMed  Article  Google Scholar 

  • Perdomo L, Beneit N, Otero YF, Escribano O, Diaz-Castroverde S, Gomez-Hernandez A et al (2015) Protective role of oleic acid against cardiovascular insulin resistance and in the early and late cellular atherosclerotic process. Cardiovasc Diabetol 14:75

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Pettersson AML, Stenson BM, Lorente-Cebrián S, Andersson DP, Mejhert N, Krätzel J, Åström G, Dahlman I, Chibalin AV, Arner P, Laurencikiene J (2013) LXR is a negative regulator of glucose uptake in human adipocytes. Diabetologia 56:2044–2054

    CAS  PubMed  Article  Google Scholar 

  • Pottecher J, Kindo M, Chamaraux-Tran TN, Charles AL, Lejay A, Kemmel V, Vogel T, Chakfe N, Zoll J, Diemunsch P, Geny B (2016) Skeletal muscle ischemia-reperfusion injury and cyclosporine a in the aging rat. Fundam Clin Pharmacol 30:216–225

    CAS  PubMed  Article  Google Scholar 

  • Rathor L, Akhoon BA, Pandey S, Srivastava S, Pandey R (2015) Folic acid supplementation at lower doses increases oxidative stress resistance and longevity in Caenorhabditis elegans. Age (Dordr) 37:113

    Article  CAS  Google Scholar 

  • Robinson MD, McCarthy DJ, Smyth GK (2010) edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26:139–140

    CAS  PubMed  Article  Google Scholar 

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

    CAS  PubMed  Article  Google Scholar 

  • Sandoval-Hernandez AG, Restrepo A, Cardona-Gomez GP, Arboleda G (2016) LXR activation protects hippocampal microvasculature in very old triple transgenic mouse model of Alzheimer's disease. Neurosci Lett 621:15–21

    CAS  PubMed  Article  Google Scholar 

  • Saraswati S, Alfaro MP, Thorne CA, Atkinson J, Lee E, Young PP (2010) Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post-MI cardiac remodeling. PLoS One 5:e15521

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Schachter F, Fauredelanef L, Guenot F, Rouger H, Froguel P, Lesueurginot L et al (1994) Genetic associations with human longevity at the Apoe and ace loci. Nat Genet 6:29–32

    CAS  PubMed  Article  Google Scholar 

  • Sharma E, Resta C, Park P (2018) A case of factitious hyperglycemia in a patient on intravenous ascorbic acid. Case Rep Endocrinol 2018:7063137

    PubMed  PubMed Central  Google Scholar 

  • Sharpless NE, Sherr CJ (2015) Forging a signature of in vivo senescence. Nat Rev Cancer 15:397–408

    CAS  PubMed  Article  Google Scholar 

  • Shen LR, Parnell LD, Ordovas JM, Lai CQ (2013) Curcumin and aging. Biofactors 39:133–140

    CAS  PubMed  Article  Google Scholar 

  • Shibamura A, Ikeda T, Nishikawa Y (2009) A method for oral administration of hydrophilic substances to Caenorhabditis elegans: effects of oral supplementation with antioxidants on the nematode lifespan. Mech Ageing Dev 130:652–655

    CAS  PubMed  Article  Google Scholar 

  • Sikora E, Bielak-Zmijewska A, Mosieniak G, Piwocka K (2010) The promise of slow down ageing may come from curcumin. Curr Pharm Des 16:884–892

    CAS  PubMed  Article  Google Scholar 

  • Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci 102:15545–15550

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Tacutu R, Craig T, Budovsky A, Wuttke D, Lehmann G, Taranukha D, Costa J, Fraifeld VE, de Magalhães JP (2013) Human ageing genomic resources: integrated databases and tools for the biology and genetics of ageing. Nucleic Acids Res 41:D1027–D1033

    CAS  PubMed  Article  Google Scholar 

  • Taniguchi A, Kataoka K, Kono T, Oseko F, Okuda H, Nagata I, Imura H (1987) Parathyroid hormone-induced lipolysis in human adipose tissue. J Lipid Res 28:490–494

    CAS  PubMed  Article  Google Scholar 

  • Tchkonia T, Morbeck DE, Zglinicki T, Deursen J, Lustgarten J, Scrable H et al (2010) Fat tissue, aging, and cellular senescence. Aging Cell 9:667–684

    CAS  PubMed  Article  Google Scholar 

  • The GTEx Consortium (2015) The genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348:648–660

    Article  CAS  Google Scholar 

  • Triplett JD, Lawn ND, Dunne JW (2019) Baclofen neurotoxicity: a metabolic encephalopathy susceptible to exacerbation by benzodiazepine therapy. J Clin Neurophysiol 36:209–212

    PubMed  Article  Google Scholar 

  • Valenzano DR, Terzibasi E, Genade T, Cattaneo A, Domenici L, Cellerino A (2006) Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Curr Biol 16:296–300

    CAS  PubMed  Article  Google Scholar 

  • Vasudevan S, Hirsch IB (2014) Interference of intravenous vitamin C with blood glucose testing. Diabetes Care 37:e93–e94

    CAS  PubMed  Article  Google Scholar 

  • Wagner A, Cohen N, Kelder T, Amit U, Liebman E, Steinberg DM, Radonjic M, Ruppin E (2015) Drugs that reverse disease transcriptomic signatures are more effective in a mouse model of dyslipidemia. Mol Syst Biol 11:791

    PubMed  Article  CAS  Google Scholar 

  • Wang J, Zhang S, Wang Y, Chen L, Zhang XS (2009) Disease-aging network reveals significant roles of aging genes in connecting genetic diseases. PLoS Comput Biol 5:e1000521

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Wang ZC, Monteiro CD, Jagodnik KM, Fernandez NF, Gundersen GW, Rouillard AD et al (2016) Extraction and analysis of signatures from the gene expression omnibus by the crowd. Nat Commun 7:12846

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Watt BE, Proudfoot AT, Vale JA (2004) Hydrogen peroxide poisoning. Toxicol Rev 23:51–57

    CAS  PubMed  Article  Google Scholar 

  • Yang YY, Gangoiti JA, Sedensky MM, Morgan PG (2009) The effect of different ubiquinones on lifespan in Caenorhabditis elegans. Mech Ageing Dev 130:370–376

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Yang M, Chen J, Su F, Yu B, Su F, Lin L, Liu Y, Huang JD, Song E (2011a) Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol Cancer 10:117

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Yang J, Manolio TA, Pasquale LR, Boerwinkle E, Caporaso N, Cunningham JM, de Andrade M, Feenstra B, Feingold E, Hayes MG, Hill WG, Landi MT, Alonso A, Lettre G, Lin P, Ling H, Lowe W, Mathias RA, Melbye M, Pugh E, Cornelis MC, Weir BS, Goddard ME, Visscher PM (2011b) Genome partitioning of genetic variation for complex traits using common SNPs. Nat Genet 43:519–525

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Yang J, Huang T, Petralia F, Long Q, Zhang B, Argmann C et al (2015) Synchronized age-related gene expression changes across multiple tissues in human and the link to complex diseases. Sci Rep 5:15145

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  • Yang JL, Huang T, Song WM, Petralia F, Mobbs CV, Zhang B et al (2016) Discover the network mechanisms underlying the connections between aging and age-related diseases. Sci Rep 6:32566

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  • Ye X, Linton JM, Schork NJ, Buck LB, Petrascheck M (2014) A pharmacological network for lifespan extension in Caenorhabditis elegans. Aging Cell 13:206–215

    CAS  PubMed  Article  Google Scholar 

  • Zhang B, Horvath S (2005) A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol 4:17

    Article  Google Scholar 

  • Zhang Q, Nogales-Cadenas R, Lin J-R, Zhang W, Cai Y, Vijg J et al (2016) Systems-level analysis of human aging genes shed new light on mechanisms of aging. Hum Mol Genet 25:2934–2947

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

JY was supported by a postdoctoral fellowship from Unity Biotechnology. ZT receives financial support from Unity Biotechnology as a consultant. This work is partially supported by NIH/NIA R01-AG055501, U24-CA210993, and a Leducq foundation award to ZT. This work was also supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.

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ZT conceived the concept of the work. JY, SP and ZT performed the analysis. JY, SP, SH, YS, ZT wrote the manuscript. All authors helped to discuss and improve the work.

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Correspondence to Zhidong Tu.

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Yang, J., Peng, S., Zhang, B. et al. Human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases. GeroScience 42, 353–372 (2020). https://doi.org/10.1007/s11357-019-00106-x

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Keywords

  • Aging
  • Age-related diseases
  • Drug repurposing
  • Network pharmacology
  • Pharmacogenomics
  • Geroscience