AGE-RELATED CHANGES IN THE METABOLIC AND COGNITIVE EFFECTS OF SYSTEMIC TNFΑ

Inflammation is essential for defence against infection or injury, but it can negatively impact the brain, particularly with ageing. TNFα plays a role in inflammatory responses during infection, sepsis, trauma, and chronic diseases. However, its effects on aged individuals remain poorly understood. This study investigated the acute impact of systemic TNFα on metabolism and cognition in adult and aged male and female mice. Mice received 250 μg/kg TNFα intraperitoneally. Activity was assessed 2.5 hours later using the open field test, and tissues were collected 5 hours post-injection. TNFα increased inflammatory markers in all animals but elicited a greater immune response in aged mice, with elevated blood cytokine levels and higher pro-inflammatory gene expression in several tissues. Blood glucose and motor activity dropped in all TNFα-treated mice, but only aged animals showed increased blood insulin and free fatty acids, suggesting a metabolic compensation attempt. However, ketogenic enzyme transcripts were downregulated in aged livers, with no rise in ketone bodies, indicating impaired lipid utilisation. Additionally, TNFα induced hypothermia exclusively in aged mice, alongside reduced CPT1A gene expression, suggesting that free fatty acids are not entering the mitochondria, and unchanged protein UCP1 levels in white adipose tissue, preventing browning and, thus thermogenesis in that tissue. Microglial gene expression was higher in the aged hippocampus, suggesting increased vulnerability to neuroinflammation. Behaviourally, TNFα impaired cognitive flexibility in aged mice, as shown in the shallow water Y-maze. These findings highlight age-related susceptibility to systemic inflammation and potential metabolic targets to mitigate TNFα-driven cognitive decline.