DNA methylation signatures reflect aging in patients with nonalcoholic steatohepatitis

Loomba, Rohit; Gindin, Yevgeniy; Jiang, Zhaoshi; Lawitz, Eric; Caldwell, Stephen H.; Djedjos, C. Stephen; Xu, Ren; Chung, Chuhan; Myers, Robert P.; Subramanian, G. Mani; Goodman, Zachary; Charlton, Michael; Afdhal, Nezam H.; Diehl, Anna Mae

doi:10.1172/jci.insight.96685

Cited by 56 publications

(51 citation statements)

References 33 publications

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“…Several lines of evidence suggest that senescence is associated with important changes in DNA methylation also affecting genes related to lipid metabolism . To investigate this hypothesis, Tryndyak et al induced NAFLD through a choline‐ and folate‐deficient diet into two different mouse strains, namely, the A/J and WSB/EiJ mice, which are known to have different susceptibility to the development of the disease.…”

Section: The Role Of Senescence In Nafld/nashmentioning

confidence: 99%

“…Loomba et al recently studied the peripheral blood DNA methylation signatures in patients with biopsy‐proven NASH and used this marker to assess age acceleration in these patients and compare it with that of healthy controls. They showed that patients with stage 3 fibrosis, scored according to the NASH Clinical Research Network (NASH CRN) classification, had increased age acceleration, which further correlated to the hepatic collagen content . A genome‐wide methylation analysis highlighted differently methylated CpG islands, which were related to alteration in the expression of a plethora of developmental pathways .…”

Section: The Role Of Senescence In Nafld/nashmentioning

confidence: 99%

“…Thus, current research efforts are focusing on whether senescence markers measured in serum, plasma or circulating cells, defined as “liquid biopsy,” may reflect disease severity and progression. These include altered expression or methylation status of senescence‐related genes, metabolomic analyses, markers of oxidative stress, or other molecular indicators of senescence, such as telomere length . Further studies should be conducted in order to prove their potential role as easily accessible biomarkers.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

“…Several lines of evidence suggest that senescence is associated with important changes in DNA methylation also affecting genes related to lipid metabolism. (40,41) To investigate this hypothesis, Tryndyak et al induced NAFLD through a choline-and folate-deficient diet into two different mouse strains, namely, the A/J and WSB/EiJ mice, which are known to have different susceptibility to the development of the disease. Indeed, the more severe steatosis, observed in the WSB/EiJ mice, as compared with the A/J mice, was accompanied by different DNA and histone methylation profiles of NAFLD-related genes and genes related to hepatic lipid accumulation and subsequent alteration in their expression.…”

Section: Evidence From Animal Studiesmentioning

confidence: 99%

“…(41) A genome-wide methylation analysis highlighted differently methylated CpG islands, which were related to alteration in the expression of a plethora of developmental pathways. (41) These data indicate that steatohepatitis may induce altered methylation profiles in a plethora of cells, apart from the hepatocytes, even in peripheral blood cells.…”

Section: The Involvement Of Senescence In Human Nafld/nashmentioning

confidence: 99%

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The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

et al. 2019

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In recent years, cellular senescence has generated a lot of interest among researchers because of its involvement in both the normal aging process and common human diseases. During senescence, cells undergo alterations that include telomere shortening, nuclear area enlargement, and genomic and mitochondrial DNA damage, leading to irreversible cell cycle arrest, and secretion of proinflammatory cytokines. Evidence suggests that the complex process of senescence is involved in the development of a plethora of chronic diseases including metabolic and inflammatory disorders and tumorigenesis. Recently, several human and animal studies have emphasized the involvement of senescence in the pathogenesis and development of liver steatosis including the progression to nonalcoholic steatohepatitis (NASH) as characterized by the additional emergence of inflammation, hepatocyte ballooning, and liver fibrosis. The development of nonalcoholic fatty liver disease (NAFLD) and its progression to NASH are commonly accompanied by several pathophysiological events including metabolic dysregulation and inflammatory phenomena occurring within the liver that may contribute to or derive from cellular senescence, implying that the latter may be both a stimulus and a consequence of the disease. Conclusion: In this review, we summarize the current literature on the impact of cellular senescence in NAFLD/NASH and discuss the effectiveness and safety of novel senolytic drugs and therapeutic options available to delay or treat the disease. Finally, we identify the open questions and issues to be addressed in the near future.

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Section: The Role Of Senescence In Nafld/nashmentioning

confidence: 99%

Section: The Role Of Senescence In Nafld/nashmentioning

confidence: 99%

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Section: Evidence From Animal Studiesmentioning

confidence: 99%

Section: The Involvement Of Senescence In Human Nafld/nashmentioning

confidence: 99%

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The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

et al. 2019

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A Fibrosis‐Independent Hepatic Transcriptomic Signature Identifies Drivers of Disease Progression in Primary Sclerosing Cholangitis

et al. 2021

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Primary sclerosing cholangitis (PSC) is a heterogeneous cholangiopathy characterized by progressive biliary fibrosis. RNA sequencing (RNA-Seq) of liver tissue from PSC patients (n=74) enrolled in a 96-week clinical trial was performed to identify associations between biological pathways that were independent of fibrosis and clinical events. The effect of fibrosis was subtracted from gene expression using a novel computational approach. The fibrosis-adjusted gene expression patterns were associated with time to first PSC-related clinical event (e.g. cholangitis, hepatic decompensation) and differential expression based on risk groups and Ingenuity Pathway Analysis (IPA) were performed. Baseline demographic data were representative of PSC: median age 48 years, 71% male, 49% with IBD, and 44% with bridging fibrosis or cirrhosis. The first principle component (PC1) of RNA-Seq data accounted for 18% of variance and correlated with fibrosis stage (ρ=-0.80; P<0.001). After removing the effect of fibrosis-related genes, PC1 was not associated with fibrosis (ρ=-0.19; P=0.11) and a semi-supervised clustering approach identified two distinct patient clusters with differential risk of time to first PSC-related event (P<0.0001). The two groups had similar fibrosis stage, hepatic collagen content and α-SMA expression by morphometry, ELF score, and serum liver biochemistry, bile acids, and IL-8 (all p>0.05). The top pathways identified by IPA were eIF2 signaling and regulation of eIF4/p70S6K signaling. Genes involved in the unfolded protein response (UPR), ATF6 and eIF2, were differentially expressed between the PSC clusters (down-regulated in the high-risk group by log-fold-changes of-0.18 [P=0.02] and-0.16 [P=0.02], respectively). Clinical events were enriched in the high versus low-risk group (38% [12/32] vs 2.4% [1/42], p<0.0001). Conclusions: Removing the contribution of fibrosis-related pathways uncovered alterations in the UPR, which were associated with liver-related complications in PSC.

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An epigenetic clock for human skeletal muscle

Voisin

Harvey

Haupt

et al. 2020

J cachexia sarcopenia muscle

118

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Background Ageing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan‐tissue epigenetic clock did not include skeletal muscle samples and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. Methods To address this, we developed a more accurate, muscle‐specific epigenetic clock based on the genome‐wide DNA methylation data of 682 skeletal muscle samples from 12 independent datasets (18–89 years old, 22% women, 99% Caucasian), all generated with Illumina HumanMethylation (HM) arrays (HM27, HM450, or HMEPIC). We also took advantage of the large number of samples to conduct an epigenome‐wide association study of age‐associated DNA methylation patterns in skeletal muscle. Results The newly developed clock uses 200 cytosine‐phosphate–guanine dinucleotides to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 cytosine‐phosphate–guanine dinucleotides of the pan‐tissue clock. The muscle clock outperformed the pan‐tissue clock, with a median error of only 4.6 years across datasets (vs. 13.1 years for the pan‐tissue clock, P < 0.0001) and an average correlation of ρ = 0.62 between actual and predicted age across datasets (vs. ρ = 0.51 for the pan‐tissue clock). Lastly, we identified 180 differentially methylated regions with age in skeletal muscle at a false discovery rate < 0.005. However, gene set enrichment analysis did not reveal any enrichment for gene ontologies. Conclusions We have developed a muscle‐specific epigenetic clock that predicts age with better accuracy than the pan‐tissue clock. We implemented the muscle clock in an r package called Muscle Epigenetic Age Test available on bioconductor to estimate epigenetic age in skeletal muscle samples. This clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle‐specific biological ageing processes.

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DNA methylation signatures reflect aging in patients with nonalcoholic steatohepatitis

Cited by 56 publications

References 33 publications

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

A Fibrosis‐Independent Hepatic Transcriptomic Signature Identifies Drivers of Disease Progression in Primary Sclerosing Cholangitis

An epigenetic clock for human skeletal muscle

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