title: Identification of miR-31-5p, miR-141-3p, miR-200c-3p, and GLT1 as human liver aging markers sensitive to donor-recipient age-mismatch in transplants.
abstract: To understand why livers from aged donors are successfully used for transplants, we looked for markers of liver aging in 71 biopsies from donors aged 12-92 years before transplants and in 11 biopsies after transplants with high donor-recipient age-mismatch. We also assessed liver function in 36 age-mismatched recipients. The major findings were the following: (i) miR-31-5p, miR-141-3p, and miR-200c-3p increased with age, as assessed by microRNAs (miRs) and mRNA transcript profiling in 12 biopsies and results were validated by RT-qPCR in a total of 58 biopsies; (ii) telomere length measured by qPCR in 45 samples showed a significant age-dependent shortage; (iii) a bioinformatic approach combining transcriptome and miRs data identified putative miRs targets, the most informative being GLT1, a glutamate transporter expressed in hepatocytes. GLT1 was demonstrated by luciferase assay to be a target of miR-31-5p and miR-200c-3p, and both its mRNA (RT-qPCR) and protein (immunohistochemistry) significantly decreased with age in liver biopsies and in hepatic centrilobular zone, respectively; (iv) miR-31-5p, miR-141-3p and miR-200c-3p expression was significantly affected by recipient age (older environment) as assessed in eleven cases of donor-recipient extreme age-mismatch; (v) the analysis of recipients plasma by N-glycans profiling, capable of assessing liver functions and biological age, showed that liver function recovered after transplants, independently of age-mismatch, and recipients apparently 'rejuvenated' according to their glycomic age. In conclusion, we identified new markers of aging in human liver, their relevance in donor-recipient age-mismatches in transplantation, and offered positive evidence for the use of organs from old donors.
authors.affiliation: DIMES- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, Via S. Giacomo12, Bologna, Italy.|CIG, Interdepartmental Center 'L. Galvani', Alma Mater Studiorum, Pzza Porta S. Donato, 1, Bologna, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Capri
authors.affiliation: Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Via Tronto 10/A, Ancona, Italy.|Center of Clinical Pathology and Innovative Therapy, INRCA-IRCCS National Institute, Via S. Margherita 5, 60124, Ancona, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Olivieri
authors.affiliation: DIMES- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, Via S. Giacomo12, Bologna, Italy.
authors.forename: Catia
authors.initials: C
authors.lastname: Lanzarini
authors.affiliation: CIG, Interdepartmental Center 'L. Galvani', Alma Mater Studiorum, Pzza Porta S. Donato, 1, Bologna, Italy.|Department of Physics and Astronomy (DIFA) and INFN Sez. Bologna, Alma Mater Studiorum, Via Berti Pichat 9/2, Bologna, Italy.
authors.forename: Daniel
authors.initials: D
authors.lastname: Remondini
authors.affiliation: DIMES- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, Via S. Giacomo12, Bologna, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Borelli
authors.affiliation: Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Via Tronto 10/A, Ancona, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Lazzarini
authors.affiliation: Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Via Tronto 10/A, Ancona, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Graciotti
authors.affiliation: Department of Biomolecular Sciences, University of Urbino 'Carlo Bo', Urbino, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Albertini
authors.affiliation: DIMES- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, Via S. Giacomo12, Bologna, Italy.|CIG, Interdepartmental Center 'L. Galvani', Alma Mater Studiorum, Pzza Porta S. Donato, 1, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bellavista
authors.affiliation: CIG, Interdepartmental Center 'L. Galvani', Alma Mater Studiorum, Pzza Porta S. Donato, 1, Bologna, Italy.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Santoro
authors.affiliation: CIG, Interdepartmental Center 'L. Galvani', Alma Mater Studiorum, Pzza Porta S. Donato, 1, Bologna, Italy.
authors.forename: Fiammetta
authors.initials: F
authors.lastname: Biondi
authors.affiliation: Center for Genome Research, Life Sciences Department, University of Modena and Reggio Emilia, Via Campi 287, Modena, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Tagliafico
authors.affiliation: Center for Genome Research, Life Sciences Department, University of Modena and Reggio Emilia, Via Campi 287, Modena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Tenedini
authors.affiliation: DIMES- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, Via S. Giacomo12, Bologna, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Morsiani
authors.affiliation: DIMES- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, Via S. Giacomo12, Bologna, Italy.
authors.forename: Grazia
authors.initials: G
authors.lastname: Pizza
authors.affiliation: 'F. Addarii' Institute of Oncology and Transplant Pathology at DIMES, S. Orsola-Malpighi Hospital, 40138, Bologna, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vasuri
authors.affiliation: 'F. Addarii' Institute of Oncology and Transplant Pathology at DIMES, S. Orsola-Malpighi Hospital, 40138, Bologna, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: D'Errico
authors.affiliation: DIMEC-Department of General Surgery and Medicine Sciences, S. Orsola-Malpighi Hospital, 40138, Bologna, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dazzi
authors.affiliation: DIMEC-Department of General Surgery and Medicine Sciences, S. Orsola-Malpighi Hospital, 40138, Bologna, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pellegrini
authors.affiliation: Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Vascular Pathology Laboratory, Via dei Monti di Creta 104, Rome, 00167, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Magenta
authors.affiliation: Department of Experimental Medicine, Sapienza, University of Rome, Viale Regina Elena 324, Rome, 00161, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: D'Agostino
authors.affiliation: Istituto Dermopatico dell'Immacolata-IRCCS, FLMM, Vascular Pathology Laboratory, Via dei Monti di Creta 104, Rome, 00167, Italy.
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
authors.affiliation: DIMEC-Department of General Surgery and Medicine Sciences, S. Orsola-Malpighi Hospital, 40138, Bologna, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Cescon
authors.affiliation: Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Via Tronto 10/A, Ancona, Italy.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Rippo
authors.affiliation: Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Via Tronto 10/A, Ancona, Italy.|Center of Clinical Pathology and Innovative Therapy, INRCA-IRCCS National Institute, Via S. Margherita 5, 60124, Ancona, Italy.
authors.forename: Antonio Domenico
authors.initials: AD
authors.lastname: Procopio
authors.affiliation: IRCCS, Institute of Neurological Sciences of Bologna, Bologna, 40139, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Franceschi
authors.affiliation: Istituto Nazionale Tumori 'Regina Elena', Via Elio Chianesi 53, Roma, 00144, Italy.
authors.forename: Gian Luca
authors.initials: GL
authors.lastname: Grazi
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D027342:Excitatory Amino Acid Transporter 2; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D050491:Glutamate Plasma Membrane Transport Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism*; D016031:Liver Transplantation; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D016615:Telomere / Q000378:metabolism; D014019:Tissue Donors; D035602:Transcriptional Elongation Factors / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D015415:Biomarkers; C447613:ELL2 protein, human; D027342:Excitatory Amino Acid Transporter 2; D050491:Glutamate Plasma Membrane Transport Proteins; C533895:MIRN141 microRNA, human; C533896:MIRN200 microRNA, human; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C493397:SLC1A2 protein, human; D035602:Transcriptional Elongation Factors; D008156:Luciferases
keywords: GLT1; N-glycans; age-mismatches; allograft; elderly donors; microRNAs; telomere length