Age-Dependent Neuroprotection and Inflammatory Responses to Mild Therapeutic Hypothermia Following Cardiac Arrest

• MTH improved survival and neurological outcomes in adult rats after CA. • Aged rats showed no benefit from MTH in survival, function, or inflammation. • IL-6 and IL-17 levels were reduced by MTH only in adult, not aged, rats. • Hippocampal neuronal apoptosis was mitigated by MTH in adults only. • Age alters neuroprotective and anti-inflammatory effects of MTH after CA. To investigate age-related differences in the neuroprotective effects and mechanisms of mild therapeutic hypothermia (MTH) after cardiac arrest (CA) to inform age-specific therapeutic strategies. Overall, 660 patients after CA were selected from the clinical databases for further validation analysis using a random forest model. 183 male rats underwent 6-min asphyxia CA and were randomized into adult (12-16 weeks) or aged (76-84 weeks) groups: sham (without CA, 37°C), sham + MTH (without CA, 33°C for 2h), control (induced CA, 37°C), and MTH (induced CA, 33°C for 2h). Over a 5-day post-return of spontaneous circulation (ROSC) period, survival, neurological function (deficit scores and locomotor activity), interleukin (IL)-17/IL-6 levels (serum and hippocampus), and CA1 neuronal apoptosis were evaluated. Clinical data analysis identified a significant interaction between age and MTH in predicting survival probability (β=-0.15, P <0.001). In adult rats, MTH significantly increased survival. Compared with the control group, adult CA rats that underwent MTH demonstrated substantially less neurological dysfunction, as evidenced by lower neurological deficit scores and improved locomotor activity throughout the 5-day post-ROSC period. MTH reduced neuronal apoptosis in the hippocampal CA1 region and decreased the levels of IL-17 and IL-6 in both serum and hippocampus. In aged rats, MTH had no significant effects on survival, neurological function, apoptosis, or inflammatory markers ( P > 0.05). Aged rats showed no benefit from MTH in survival, function, or inflammation compared to adult rats. Age alters the neuroprotective and anti-inflammatory effects of MTH after CA.