Mice Undergo Organ-Specific Transcriptional and Metabolic Remodeling During Late Adolescence

Mouse models aimed at deciphering human aging have typically focused on early development or late-life stages. Much less is known about the transition from late adolescence to young adulthood, spanning 8 to 12 weeks of age. Here, we show that C57Bl6 mice undergo a comprehensive developmental transition characterized by significant transcriptional and metabolic reprogramming during this time. Transcriptional analysis revealed substantial, organ-specific changes: the heart shifts toward a maintenance-focused phenotype with down-regulated oxidative phosphorylation (OXPHOS) and increased expression of genes supporting structural remodeling. Conversely, the kidney adopts an immunologically active state, reflecting progressive immune cell colonization, while the liver shifts from a hematopoietic role to one dominated by lipid metabolism, detoxification, and ketogenesis. These transcriptional changes correspond to a coherent metabolic maturation driven by the gut-liver axis. Intestinal maturation enhances lipid absorption and microbial fermentation, leading to increased circulating levels of short-chain fatty acids, poly-unsaturated glycerolipids, and sphingomyelins. Elevated hepatic production of ketone bodies, driven by up-regulated fatty acid metabolism genes, provides an efficient alternative energy substrate for peripheral tissues like the heart. Urinary metabolite profiles, marked by increased acylglycines and tricarboxylic acid (TCA) cycle intermediates, further confirm heightened mitochondrial energy turnover and fatty acid β-oxidation. Collectively, this coordinated maturation from 8 to 12 weeks signifies the transition from a highly plastic developmental state to a stable, energy-efficient, and metabolically flexible adult phenotype.