Epigenetic Information Loss and Chronosenescence in Liver Aging: From Molecular Mechanisms to Therapeutic Interventions.

Liver aging involves progressive functional decline and increased susceptibility to metabolic diseases. Emerging evidence supports the view that some aspects of liver aging reflect partially reversible disruption of epigenetic and circadian regulatory programs, rather than exclusively irreversible molecular damage. This review focuses on two interlinked drivers: epigenetic information loss and chronosenescence, defined as age-related deterioration of circadian clock robustness. The NAD⁺/SIRT1 axis is discussed as a central hub connecting these processes with energy metabolism. This comprehensive review synthesizes evidence from foundational studies and recent advances in single-cell multiomics, spatial transcriptomics, and CRISPR epigenetic editing technologies. It also evaluates emerging therapeutic strategies, including lifestyle intervention, NAD⁺ restoration, chronotherapy, partial cellular reprogramming, chemical reprogramming, and extracellular vesicle-based approaches, with emphasis on their current translational maturity and limitations. The integrated analysis highlights the spatial heterogeneity of liver aging and supports mechanistic links between epigenetic remodeling, circadian disruption, NAD⁺ decline, inflammation, and metabolic dysfunction. Experimental studies suggest that selected regulatory features of liver aging can be modified, but direct causal evidence in humans remains limited, and most rejuvenation-oriented strategies remain preclinical or early translational. This review establishes a unified framework for understanding liver aging as a disorder of regulatory information and temporal coordination. It provides a cautious translational roadmap for identifying modifiable nodes in liver aging while emphasizing that clinical application will require rigorous validation of safety, durability, delivery, patient selection, and long-term outcomes.