Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature

Abstract

The feasibility of liver transplantation from old healthy donors suggests that this organ is able to preserve its functionality during aging. To explore the biological basis of this phenomenon, we characterized the epigenetic profile of liver biopsies collected from 45 healthy liver donors ranging from 13 to 90 years old using the Infinium HumanMethylation450 BeadChip. The analysis indicates that a large remodeling in DNA methylation patterns occurs, with 8823 age-associated differentially methylated CpG probes. Notably, these age-associated changes tended to level off after the age of 60, as confirmed by Horvath's clock. Using stringent selection criteria we further identified a DNA methylation signature of aging liver including 75 genomic regions. We demonstrated that this signature is specific for liver compared to other tissues and that it is able to detect biological age-acceleration effects associated with obesity. Finally we combined DNA methylation measurements with available expression data. Although the intersection between the two omic characterizations was low, both approaches suggested a previously unappreciated role of epithelial-mesenchymal transition and Wnt signaling pathways in the aging of human liver.

Optimizing the Use of Geriatric Livers for Transplantation in the Eurotransplant Region

“…In this study, we have shown that the risk of graft loss increases linearly from a donor age of 25 up to 80 years old. The risk of livers from donors of 80 years may increase nonlinearly and suggests that these organs reach the outer limits of biological flexibility despite their regenerative capacity …”

Methylation signatures in peripheral blood are associated with marked age acceleration and disease progression in patients with primary sclerosing cholangitis

“…For instance, successful liver transplantation from chronologically old, but biologically 'fit' donors reflects the clear distinction between biological vs. chronological age. 9 The converse is also true as the intrinsic rate of the DNAm clock can be altered by diseases that involve the liver. HIV and obesity predispose to increased liver injury, and both accelerate the epigenetic clock more than would be expected from agematched control specimens.…”

Noncoding RNA in Liver Regeneration—From Molecular Mechanisms to Clinical Implications

“…On the one hand, there are significant changes in expression of crucial proteins like Yap or Sirt1, and lncRNAs in the aged mice and humans. [196][197][198] On the other hand, there is a clinical evidence that orthotopic liver transplants from aged donors are comparable to those from young donors. 199 We propose significant progress on the roles of ncRNA in aging liver as many transplants in clinic are from people more than 70 to 80 years old.…”