Research published in Immunity & Ageing has shown that obesity has significant, aging-associated effects on behavior and immunity in the brains of mice.
Known effects on humans and mice
The researchers introduce this study by discussing human studies. It is well known that obesity is a risk factor for severe metabolic disorders, such as diabetes and cardiovascular disease , and dementia later in life .
While such longitudinal studies are highly informative, they do not document any of the fundamental biology involved. Previous research has been conducted in that area, showing that obesity harms the hippocampus  and encourages inflammation  in mouse models. The effects of aging have also been heavily documented in these models as well, illustrating the well-known phenomenon of inflammaging .
The effects of obesity on aged mice have also been documented, showing a broad variety of harms to the brain , including gene expressions associated with Alzheimer’s disease . In this paper, the researchers build on that work by analyzing mice of different ages in an effort to determine how obesity and aging interact.
An analysis of four groups
In this study, the researchers used four groups: 16-week-old mice fed a standard diet (SD), 16-week-old fed a high-fat diet (HFD) to induce obesity, 24-week-old mice fed an SD, and 24-week-old mice on the HFD.
This paper began with a hippocampal gene expression analysis. Eight weeks of aging were shown to affect 729 genes, and the change in diet was shown to affect 886 genes. 216 of these genes were the same ones: in these cases, obesity was shown to affect the hippocampus in approximately the same way that aging did. Many of these pathways were related to metabolic dysfunction, and others were related to neurodegenerative diseases such as Parkinson’s, Huntington’s, and Alzheimer’s.
A more involved look showed more counterintuitive data. In many cases, such as in genes related to lymphocyte function and immune cell activation, aging and HFD were shown to independently increase their expression; however, the aged HFD mice had decreased expression instead.
The effects on body size were largely predictable. Both aging and a high-fat diet increase fat mass in mice. However, aged mice fed the high-fat diet were not significantly larger than their younger counterparts fed the same diet, and their individual fat cells were not found to be larger either. They did, however, have significantly worse problems handling glucose; the effects of aging and a high-fat diet were shown to combine in this respect.
Effects on the brain
While neither aging nor a high-fat diet were shown to significantly increase pro-inflammatory cytokines in the hippocampus, aged HFD mice had more immune cells in the brain than their SD counterparts did. The data showed that aging slightly increases this as well, but not to the level of statistical significance. The researchers noted that this obesity-associated increase in microglia is in line with previous research in other animal models .
Obesity also caused a more pronounced fear response in these mice. HFD mice in both groups were shown to learn a Pavlovian fear association more quickly; normally, aging slows the development of this learned response. Aging also slows the gradual loss of this response when it is being conditioned out of the mice; however, HFD mice, particularly aged HFD mice, retained their fear responses significantly longer.
While some of the data is notably counterintuitive and bears further investigation, this study largely confirms what is known about obesity and its effects on the brain. Some of this information may be specific to mice; for example, the effects on fear response did not apply to rats . However, this study adds to the body of research showing that obesity has significant, aging-associated, and largely negative effects on the brains of mammals.
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