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 levels of saturated fat and refined carbohydrates and low dietary fiber, are closely associated with cognitive decline, particularly among older adults. This study aimed to elucidate the specific contributions of macronutrients and the underlying mechanisms of these effects by examining the impact of short-term exposure to refined-ingredient diets (RDs) with varying fat and sugar content on memory, mitochondrial function, and metabolic signaling in young adult and aged male rats.

A critical finding indicates that amygdala-dependent memory was significantly impaired in aged rats across all RDs, irrespective of their fat or sugar content, suggesting a particular vulnerability of the aging amygdala to refined dietary components. Conversely, impairments in hippocampal-dependent memory were observed only in aged rats consuming a high-fat, low-sugar RD.

Functional mitochondrial assays demonstrated marked reductions in oxygen consumption in both amygdalar and hippocampal mitochondria isolated from aged rats exposed to RDs. Further analyses revealed that aged microglia exhibited a pronounced susceptibility to RDs, characterized by widespread suppression of mitochondrial respiration and limited metabolic flexibility, while astrocytes and synaptic mitochondria displayed more region- and age-specific responses.

Consistent with prior research, all RDs were devoid of dietary fiber, leading to a rapid and significant depletion of butyrate, a microbial-derived short-chain fatty acid, in both the gut and circulation of aged animals. Proteomic and phosphoproteomic analyses uncovered diet-induced disruptions in mitochondrial proteins and synaptic signaling pathways, notably affecting complex I subunits and glutamate receptor signaling. Collectively, these findings underscore the heightened sensitivity of the aged amygdala to refined dietary exposure and illuminate potential microbial, metabolic, and inflammatory pathways contributing to diet-induced cognitive decline. [NPID: Amygdala, cognitive decline, refined diet]

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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