Isoflurane and Surgical Stress Disrupt Fatty Acid and Carbon Metabolism, Leading to Cardiomyopathy in Aged Mice

Aging alters cardiac resilience to anesthetic and surgical stress, yet the molecular basis for these effects remain poorly understood. To define age-dependent transcriptional responses, we profiled cardiac gene expression across young adult (3 m), late middle-aged (17 m), and old mice (27 m) following 2 h isoflurane and operative (Iso/Op) exposure. Across all age groups, 24 h after cessation, Iso/Op induced distinct transcriptional signatures relative to the sham, with conserved perturbations in oxidative stress responses, Ca²⁺ handling, hypertrophy-associated signaling, and energy metabolism. In 3 m hearts, transcriptional alterations were characterized by dysregulation of small-molecule catabolism, fatty acid metabolism, endoplasmic reticulum processing, and cytoskeletal organization. In 17 m hearts, lipid metabolic disruption was amplified and accompanied by suppression of muscle system and calcium signaling pathways. In 27 m hearts, Iso/Op robustly activated PPAR and AMPK signaling and fatty acid catabolic programs while downregulating pathways governing contractility, actin organization, and morphogenesis, consistent with age-associated maladaptive metabolic reprogramming. To assess persistence, we analyzed a longitudinal cohort of 20 m mice five weeks after exposure and observed sustained transcriptomic remodeling driven predominantly by isoflurane, including mitochondrial dysfunction and altered expression of genes linked to diabetic cardiomyopathy, extracellular matrix integrity, and neurodegeneration-associated pathways. Together, these data suggest that isoflurane-based perioperative stress can produce age-amplified and durable metabolic and structural cardiac remodeling, implicating impaired lipid utilization and mitochondrial homeostasis as potential mechanisms of long-term cardiovascular vulnerability.