Aging Effects on Lipid Metabolism in Response to Traumatic Brain Injury

Traumatic brain injury (TBI) is highly prevalent among very young and older adults, with poorer outcomes and longer recovery in aged individuals. The brain is a lipid-rich organ and high rates of membrane remodeling occur during recovery, yet remain poorly delineated, especially in aged. To determine the impact of age on lipid metabolism during TBI recovery, TBI was induced by control cortical impact in 3 (young) and 20 (aged) month-old mice. The ipsilateral cortex was harvested at 1-, 3-, 7-, and 28-day post injury (dpi) for analysis of gene expression, membrane lipidomics, total lipid fatty acid profile, and intermediates of fatty acid β-oxidation, acylcarnitines. Lipid metabolizing genes were largely downregulated in response to TBI in young mice, yet remained unchanged or were increased in aged mice, resulting in significantly higher expression in aged compared to young. TBI increased acylcarnitines by a robust ~3-fold in both young and aged cohorts acutely following injury and restored to sham levels by day 28. Phospholipidome compositional analysis reveals largest changes in the aged mice at 28 dpi. Aged mice phospholipid profiles shifted towards higher mono- and di- unsaturated and lower saturated and highly polyunsaturated species. Phospholipids with 4 unsaturated bonds, predicted to contain arachidonic acid, tended to increase post-TBI, whereas species containing 6 unsaturated bonds, predicted to contain docosahexaenoic acid (DHA) steadily declined during recovery. Total fatty acid analysis confirmed decreased DHA at 28 dpi in aged mice and more severely after TBI. In summary, TBI in aged led to a loss of transcriptional repression, more profound phospholipid change, earlier upregulation of acylcarnitines, and significant decrease in brain DHA content. Together, these data suggest that TBI occurrence in aging, compared to young, has less impact on gene expression of lipid metabolic genes but greater impact on lipid content.