Longevity-driven hepatic transcriptional programs mediate resilience to diet-induced liver injury in Ames dwarf mice

The liver plays a central role in regulating systemic metabolism, and its function declines with age, contributing to increased susceptibility to metabolic diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by hepatic lipid accumulation and inflammation, is an early manifestation of liver dysfunction strongly associated with aging, insulin resistance, and high-fat diet (HFD) consumption. Ames Dwarf mice, which are growth hormone (GH)-deficient and long-lived, retain insulin sensitivity and exhibit resistance to age-related metabolic decline, making them an ideal model to study hepatic protection mechanisms. In this study, male and female Ames Dwarf and wildtype (WT) mice were fed either a standard diet or HFD for 12 weeks. WT males developed classical features of MASLD, including hepatic steatosis, hepatocyte ballooning, and elevated levels of inflammatory cytokines (IL-1β, MCP-1, IL-2, and IL-4). In contrast, Ames Dwarf mice exhibited minimal liver pathology, reduced lipid accumulation, and limited cytokine induction. Transcriptomic profiling revealed that WT mice upregulated genes involved in inflammation and proliferation, while Ames Dwarf mice showed activation of protective metabolic pathways (PPAR and AMPK) and suppression of lipogenic and fibrotic gene programs. Notably, female Ames Dwarf mice displayed the strongest resistance to HFD-induced changes, with minimal transcriptomic alterations. These findings suggest that disrupted GH signaling in Ames Dwarf mice leads to a reprogrammed hepatic response that preserves metabolic health and protects against MASLD, highlighting potential links between aging, GH signaling, and liver resilience.