Abstract

Aging and nutrient stress reshape the physiological landscape of metabolic organs, yet how these factors interact across development remains unclear. The liver and gallbladder, central to hepatobiliary function, may exhibit distinct transcriptional responses to aging and fasting, reflecting their divergent roles in metabolism and immune regulation. We performed bulk RNA sequencing of mouse liver and gallbladder tissues across three developmental stages (P27, 2M, 21M) under both fed and fasted conditions. We applied Mfuzz clustering and WGCNA to delineate temporal gene expression patterns and age-associated co-expression modules. The liver showed a gradual transcriptional shift from proliferative to immune-dominant states with age, while the gallbladder exhibited biphasic remodeling: early immune activation coupled with metabolic suppression, followed by reactivation of lipid metabolism in old age. Fasting induced conserved lipid catabolism in both organs, but age-specific regulatory modules revealed distinct adaptive mechanisms. Aged liver activated histone remodeling and translational programs while suppressing lipid metabolism. In contrast, the aging gallbladder displayed reduced insulin responsiveness and autophagic capacity, coupled with enhanced extracellular matrix reorganization. These findings reveal organ- and age-specific transcriptional strategies underlying hepatobiliary adaptation to aging and fasting, offering insight into the developmental logic and decline of metabolic resilience across the lifespan.