Scientists report that a low-fat diet in combination with limited caloric consumption prevents activation of the brain's microglia in aging mice. The study (“Low-Fat Diet With Caloric Restriction Reduces White Matter Microglia Activation During Aging”), published in Frontiers in Molecular Neuroscience, also finds that exercise is significantly less effective than caloric restriction in preventing these age-related changes.

“Rodent models of both aging and obesity are characterized by inflammation in specific brain regions, notably the corpus callosum, fornix, and hypothalamus. Microglia, the resident macrophages of the central nervous system, are important for brain development, neural support, and homeostasis. However, the effects of diet and lifestyle on microglia during aging are only partly understood. Here, we report alterations in microglia phenotype and functions in different brain regions of mice on a high-fat diet (HFD) or low-fat diet (LFD) during aging and in response to voluntary running wheel exercise. We compared the expression levels of genes involved in immune response, phagocytosis, and metabolism in the hypothalamus of 6-month-old HFD and LFD mice. We also compared the immune response of microglia from HFD or LFD mice to peripheral inflammation induced by intraperitoneal injection of lipopolysaccharide (LPS),” write the investigators.

“Finally, we investigated the effect of diet, physical exercise, and caloric restriction (40% reduction compared to ad libitum intake) on microglia in 24-month-old HFD and LFD mice. Changes in diet caused morphological changes in microglia, but did not change the microglia response to LPS  [lipopolysaccharide]-induced systemic inflammation. Expression of phagocytic markers (i.e., Mac-2/Lgals3, Dectin-1/Clec7a, and CD16/CD32) in the white matter microglia of 24-month-old brain was markedly decreased in calorically restricted LFD mice. In conclusion, LFD resulted in reduced activation of microglia, which might be an underlying mechanism for the protective role of caloric restriction during aging-associated decline.”

“Obesity and aging are both prevalent and increasing in societies worldwide, but the consequences for the central nervous system are not well understood,” says Bart Eggen, Ph.D., lead author of the study and a researcher at the University Medical Center Groningen, The Netherlands. “We determined if a high- or low-fat diet, in combination with exercise and food restriction, impacted microglia during aging in mice.”

Microglia help maintain the integrity and normal functioning of brain tissue. Dysfunction of these cells, as may occur in disease, is linked to neurodevelopmental disorders and neurodegenerative conditions. Aging is also associated with inflammation driven by microglia in specific regions of the brain, but it is unclear whether diet or lifestyle can influence this process. 

Dr. Eggen and his collaborators investigated the impact of high- and low-fat diets on inflammation and microglial markers in the hypothalamus of 6-month-old mice. They further looked at the effect of low- or high-fat diets on the microglia of 2-year-old mice, which were also given a lifelong exercise regime (voluntary running wheel) or lifelong restricted diets (a 40% reduction in calories). 

“Aging-induced inflammatory activation of microglia could only be prevented when mice were fed a low-fat diet in combination with limited caloric intake,” says Dr. Eggen. “A low-fat diet per se was not sufficient to prevent these changes.”

The researchers also found that exercise was significantly less effective than caloric restriction at preventing these changes, although work by others has shown that exercise is associated with reducing the risk of other diseases.

Dr. Eggen points out that there is still much more work needed to understand the meaning of these findings. In their study, mice were only given one type of diet throughout their lives. It remains unclear how changing between diets would alter these results—for example whether switching to a low-fat diet could undo the negative consequences of a high-fat, unrestricted diet. Further studies are also needed to determine how these changes correspond to the cognitive performance of the mice. 

“Nevertheless, these data do show that, in mice, the fat content of a diet is an important parameter in terms of the detrimental effects of aging on the brain, as well as caloric intake,” says Dr.  Eggen. “Only when fat content and caloric intake are limited can aging-induced changes in microglia be prevented.”

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