Reversible and Causal Epigenetic Information Loss in Liver Aging and Disease

Abstract The loss of epigenetic information has been proposed as a driver of aging and diseases, but the reversibility and causality of this process remain underexplored. Here we analyze liver-unique methylation sites - genomic loci that show distinct methylation patterns in the liver compared to other tissues. Upon disease progression, these sites overwhelmingly regress toward the pan-tissue average. In addition, we demonstrate that this regression also occurs in a majority of these sites during normal aging. Using Mendelian randomization analysis, we identify significant enrichment of liver-unique methylation sites in causal aging-associated loci, particularly sites that are highly methylated in healthy liver. Remarkably, repeated fasting, a metabolic intervention known to improve liver function, partially restores the liver-unique methylation patterns at these sites. This restoration also occurs in isolated hepatocytes subjected to fasting-mimicking conditions, suggesting the effect is cell-autonomous rather than due to changes in tissue composition. The liver-unique methylation sites are enriched for binding sites of key metabolic transcription factors and show significant overlap with genetic variants associated with liver disease risk, suggesting a mechanistic link between epigenetic information loss and liver dysfunction. Our findings establish epigenetic information loss as both a marker and mediator of liver aging and disease, while demonstrating its potential reversibility through metabolic interventions. Graphical abstract: Reversible information loss at liver-unique methylation sites Liver-unique sites, showing higher (UH) or lower (UL) methylation levels, regress to the pan-tissue average upon aging and disease. UH are enriched for methylation sites causal to the aging process, while UL are enriched for liver-specific enhancers and PPAR-α binding sites. Upon repeated fasting, both UL and UH diverge away from the pan-tissue average, partially restoring the more youthful and disease-free epigenetic state. Competing Interest Statement The authors have declared no competing interest.