Isoflurane and Surgical Stress Disrupt Fatty Acid and Carbon Metabolism Leading to Cardiomyopathy.

Aging alters cardiac resilience to anesthetic and surgical stress, yet the molecular basis of these effects remains poorly understood. To define age-dependent cardiac transcriptional responses to isoflurane exposure and operative (ISO/OP) stress, we analyzed gene expression profiles across young adult (3m), late middle-aged (17m), and geriatric mice (27m) following short-term 2 h ISO/OP exposure. At 24 h after cessation, all age groups exhibited distinct cardiac transcriptional signatures separating ISO/OP from sham controls. In young adult hearts, transcriptional alterations 24 hours after cessation of ISO/OP were characterized by dysregulation of small molecule catabolic processes, fatty acid metabolism, disruptions to protein processing in endoplasmic reticulum and cytoskeletal organization. Late middle-aged mice displayed amplified perturbations in lipid metabolism alongside suppression of muscle system and calcium signaling pathways, while old mice showed robust activation of PPAR and AMPK signaling and downregulation of genes governing contractility and morphogenesis. In contrast, geriatric mice showed upregulation of fatty acid metabolic pathways, robust activation of PPAR and AMPK signaling, coupled with suppression of muscle differentiation and actin organization following ISO exposure, indicating a maladaptive metabolic reprogramming. Overlapping DEGs across all age groups converged on pathways regulating oxidative stress, Ca