Aging and age-related diseases are associated with cellular stress, metabolic imbalance, oxidative stress, and neuroinflammation, accompanied by cognitive impairment. Lifestyle factors such as diet, sleep fragmentation, and stress can potentiate damaging cellular cascades and lead to an acceleration of brain aging and cognitive impairment. High-fat diet (HFD) has been associated with obesity, metabolic disorders like diabetes, and cardiovascular disease. HFD also induces neuroinflammation, impairs learning and memory, and may increase anxiety-like behavior. Effects of a HFD may also vary between sexes. The interaction between Age- and Sex- and Diet-related changes in neuroinflammation and cognitive function is an important and poorly understood area of research. This study was designed to examine the effects of HFD on neuroinflammation, behavior, and neurodegeneration in mice in the context of aging or sex differences. In a series of studies, young (2-3 months) or old (12-13 months) C57BL/6J male mice or young male and female C57Bl/6J mice were fed either a standard diet (SD) or a HFD for 5-6 months. Behavior was assessed in Activity Chamber, Y-maze, Novel Place Recognition, Novel Object Recognition, Elevated Plus Maze, Open Field, Morris Water Maze, and Fear Conditioning. Post-mortem analyses assessed a panel of inflammatory markers in the plasma and hippocampus. Additionally, proteomic analysis of the hypothalamus, neurodegeneration, neuroinflammation in the locus coeruleus, and neuroinflammation in the hippocampus were assessed in a subset of young and aged male mice. We show that HFD increased body weight and decreased locomotor activity across groups compared to control mice fed a SD. HFD altered anxiety-related exploratory behavior. HFD impaired spatial learning and recall in young male mice and impaired recall in cued fear conditioning in young and aged male mice, with no effects on spatial learning or fear conditioning in young female mice. Effects of Age and Sex were observed on neuroinflammatory cytokines, with only limited effects of HFD. HFD had a more significant impact on systemic inflammation in plasma across age and sex. Aged male mice had induction of microglial immunoreactivity in both the locus coeruleus (LC) and hippocampus an effect that HFD exacerbated in the hippocampal CA1 region. Proteomic analysis of the hypothalamus revealed changes in pathways related to metabolism and neurodegeneration with both aging and HFD in male mice. Our findings suggest that HFD induces widespread systemic inflammation and limited neuroinflammation. In addition, HFD alters exploratory behavior in male and female mice, and impairs learning and memory in male mice. These results provide valuable insight into the impact of diet on cognition and aging pathophysiology.
