ABSTRACT: Elderly patients exhibit heightened susceptibility to postoperative complications following general anesthesia and surgery, yet the molecular mechanisms driving this age-dependent vulnerability remain poorly defined. We performed RNA sequencing on olfactory bulb (OB), hippocampus (HI), lung, and spleen from young (3-month, m), late middle-aged (17m), and geriatric (27m) male C57BL/6 mice 24 hours after 2 hours of exposure to isoflurane anesthesia and laparotomy (ISO/OP). Short-term ISO/OP elicited pronounced, age-dependent transcriptional remodeling across tissues. Late middle-aged mice exhibited robust activation of stress- and metabolism-associated pathways in the OB and HI, accompanied by suppression of lipid, synaptic, and structural maintenance programs. In contrast, young adults displayed limited responses, characterized by modest and adaptive synaptic remodeling in the HI. Peripheral organs showed a parallel age-dependent divergence. Late middle-aged mice exhibited amplified immune and inflammatory signaling in the lung and spleen alongside suppression of structural, regulatory, and metabolic homeostatic programs, whereas young adults demonstrated attenuated, metabolically adaptive transcriptional responses. Circulating extracellular vesicles (EVs) mirrored tissue-level shifts, indicating a systemic transition from adaptive plasticity in 3m to stress and immune dominant signaling by 17m. Geriatric mice displayed a distinct response pattern, characterized by activation of stress and detoxification programs in brain tissues, altered circadian gene expression in lung and spleen, and extensive remodeling of EV protein cargo enriched for inflammatory and growth factor-related signatures. Together, these findings indicate that late middle-age is associated with amplified peri-anesthetic biological reactivity across central and peripheral systems, suggesting an under-recognized window for perioperative risk stratification and preventative intervention.
