TY - JOUR
T1 - 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
AU - Capri, Miriam
AU - Olivieri, Fabiola
AU - Lanzarini, Catia
AU - Remondini, Daniel
AU - Borelli, Vincenzo
AU - Lazzarini, Raffaella
AU - Graciotti, Laura
AU - Albertini, Maria Cristina
AU - Bellavista, Elena
AU - Santoro, Aurelia
AU - Biondi, Fiammetta
AU - Tagliafico, Enrico
AU - Tenedini, Elena
AU - Morsiani, Cristina
AU - Pizza, Grazia
AU - Vasuri, Francesco
AU - D'Errico, Antonietta
AU - Dazzi, Alessandro
AU - Pellegrini, Sara
AU - Magenta, Alessandra
AU - D'Agostino, Marco
AU - Capogrossi, Maurizio C
AU - Cescon, Matteo
AU - Rippo, Maria Rita
AU - Procopio, Antonio Domenico
AU - Franceschi, Claudio
AU - Grazi, Gian Luca
N1 - © 2016 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
PY - 2016/12/20
Y1 - 2016/12/20
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1111/acel.12549
DO - 10.1111/acel.12549
M3 - Article
C2 - 27995756
VL - 16
SP - 262
EP - 272
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
IS - 2
ER -