Evidence mapPaperPMID 40324540Full record

ArticleMechanisms of ageing and development2025

Transcriptomic and epigenomic signatures of liver metabolism and insulin sensitivity in aging mice.

John T González, Olivia H Scharfman, Wanling Zhu, Jessica Kasamoto, Victoria Gould, Rachel J Perry, Albert T Higgins-Chen

Abstract read
In one paragraph

Article in Mechanisms of ageing and development, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors.

John T GonzálezDepartment of Pathology, Yale University School of Medicine, New Haven, CT, USA.
Olivia H ScharfmanDepartment of Pathology, Yale University School of Medicine, New Haven, CT, USA.
Wanling ZhuDepartment of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, USA; Department of Endocrinology & Metabolism, Yale School of Medicine, New Haven, CT, USA.
Jessica KasamotoProgram in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
Victoria GouldAltos Labs, Institute of Computation, San Diego, CA 92114, USA.
Rachel J PerryDepartment of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT, USA; Department of Endocrinology & Metabolism, Yale School of Medicine, New Haven, CT, USA. Electronic address: rachel.perry@yale.edu.
Albert T Higgins-ChenDepartment of Pathology, Yale University School of Medicine, New Haven, CT, USA; Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA; Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA. Electronic address: a.higginschen@yale.edu.

Funding

Defining the Role of Renal Gluconeogenesis in Renal Cell CarcinomaR37CA258261 · NCI · YALE UNIVERSITY · 2023 to 2025
$1.3M
Yale Center for Metabolic Phenotyping in Live Models of Obesity and DiabetesU2CDK134901 · YALE UNIVERSITY · 2025 to 2025
$763k
NCI NIH HHS R37 CA258261NIA NIH HHS R01 AG065403NIDDK NIH HHS U2C DK134901
6 · The paper itself

Abstract

Age-related declines in insulin sensitivity and glucose metabolism contribute to metabolic disease. Despite the liver's central role in glucose homeostasis, a comprehensive phenotypic characterization and concurrent molecular analysis of insulin resistance and metabolic dysfunction in the aging liver is lacking. We characterized hepatic insulin resistance and mitochondrial metabolic defects through metabolic cage, hyperinsulinemic-euglycemic clamp, and tracer studies paired with transcriptomic and DNA methylation analyses in young and aged male mice. Aged mice exhibited benchmark measures of whole body and liver insulin resistance. Aged mice showed lower pyruvate dehydrogenase flux, decreased fatty acid oxidation and citrate synthase fluxes, and increased pyruvate carboxylase flux under insulin-stimulated conditions. Molecular analysis revealed age-related changes in metabolic genes Pck1, Socs3, Tbc1d4, and Enpp1. Unsupervised network analysis identified an intercorrelated phenotype module (ME-Glucose), RNA module, and DNA methylation module. The DNA methylation module was enriched for lipid metabolism pathways and TCF-1 binding, while the RNA module was enriched for MZF-1 binding and regulation by miR-155-5p. Protein-protein interaction network analysis revealed interactions between module genes and canonical metabolic pathways, highlighting genes including Ets1, Ppp1r3b, and Enpp3. This study reveals novel genes underlying age-related hepatic insulin resistance as potential targets for metabolic interventions to promote healthy aging.

Indexed as

AgingEpigenesis, GeneticInsulin ResistanceLiverTranscriptomeAnimalsDNA MethylationEpigenomicsMaleMiceDNA methylationInsulin resistanceMetabolic flux analysisMitochondrial dysfunctionTricarboxylic acid (TCA) cycle

Identifiers

PMID40324540
PMCPMC12151592

What Socratic holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.