Open AccessIdentification of miR‐31‐5p, miR‐141‐3p, miR‐200c‐3p, and GLT 1 as human liver aging markers sensitive to donor–recipient age‐mismatch in transplants
Author(s) -
Capri Miriam,
Olivieri Fabiola,
Lanzarini Catia,
Remondini Daniel,
Borelli Vincenzo,
Lazzarini Raffaella,
Graciotti Laura,
Albertini Maria Cristina,
Bellavista Elena,
Santoro Aurelia,
Biondi Fiammetta,
Tagliafico Enrico,
Tenedini Elena,
Morsiani Cristina,
Pizza Grazia,
Vasuri Francesco,
D'Errico Antonietta,
Dazzi Alessandro,
Pellegrini Sara,
Magenta Alessandra,
D'Agostino Marco,
Capogrossi Maurizio C.,
Cescon Matteo,
Rippo Maria Rita,
Procopio Antonio Domenico,
Franceschi Claudio,
Grazi Gian Luca
Publication year - 2017
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12549
Subject(s) - biology , transcriptome , microrna , ageing , liver transplantation , andrology , economic shortage , messenger rna , immunohistochemistry , real time polymerase chain reaction , medicine , gene expression , transplantation , immunology , gene , genetics , linguistics , philosophy , government (linguistics)
Summary 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 micro RNA s (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 GLT 1, a glutamate transporter expressed in hepatocytes. GLT 1 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.