The aged amygdala’s unique sensitivity to refined diets, independent of fat or sugar content: A brain region and cell type-specific analysis

Western-style diets characterized by high saturated fats and refined carbohydrates, and low dietary fiber, have been associated with cognitive decline, particularly in the aging population. This research explores the effects of short-term exposure to refined diets (RDs) with varying fat and sugar levels on memory, mitochondrial function, and metabolic signaling in young adult and aged male rats.

A key finding indicates that amygdala-dependent memory was universally impaired in aged rats across all RDs, suggesting a unique vulnerability of the aging amygdala to refined dietary components. Conversely, impairments in hippocampal-dependent memory were observed exclusively in aged rats consuming a high-fat, low-sugar RD.

Functional mitochondrial assays disclosed significant reductions in oxygen consumption within amygdalar and hippocampal mitochondria of aged rats exposed to RDs. Further analyses revealed that aged microglia exhibited pronounced susceptibility, demonstrating widespread suppression of mitochondrial respiration and limited metabolic flexibility. Astrocytes and synaptic mitochondria displayed effects that were more specific to region and age.

All RDs lacked dietary fiber, leading to rapid depletion of butyrate, a short-chain fatty acid produced by microbial activity, particularly in aged subjects. Proteomic and phosphoproteomic analyses uncovered diet-induced disruptions in mitochondrial proteins and synaptic signaling pathways, notably involving complex I subunits and glutamate receptor signaling. Ultimately, these findings underscore the heightened sensitivity of the aged amygdala to refined dietary exposure and illuminate the microbial, metabolic, and inflammatory pathways that may contribute to diet-induced cognitive decline. [NPID: Western-style diet, amygdala, hippocampus, mitochondria, SFCAs]

Year: 2026

Reference: Butler, M. J., Blackwell, J. A., Sanchez, A. A., Sanders, H. F., Kolonay, D. W., Jantsch, J., Muscat, S. M., Caetano-Silva, M. E., Shrestha, A., Yun Lim, C. K., Mackey-Alfonso, S. E., Alvarez, B. D., McCusker, R. H., Allen, J. M., Baskin, K. K., & Barrientos, R. M. (2026). The aged amygdala’s unique sensitivity to refined diets, independent of fat or sugar content: A brain region and cell type-specific analysis. Brain, Behavior, and Immunity, 132, 106220. https://doi.org/10.1016/j.bbi.2025.106220

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