High-fat diet accelerates aging-related memory loss in rats

A recent study published in the journal Neurobiology of Aging determines whether a high-fat diet contributes to memory decline in older people compared to aging alone.

Study: High-fat diet and aging-associated memory impairments persist in the absence of microglia in female rats. Image Credit: beats1 / Shutterstock.com

Diet and aging

Highly processed food products, which are high in energy but low in nutrition, have become increasingly popular worldwide.

However, the increased consumption of these food products has led to growing rates of obesity and associated diseases like high blood pressure and type 2 diabetes mellitus, both of which are risk factors for cardiovascular disease (CVD) and cancer. Obesity is also associated with anxiety, depression, worsening memory, poor executive function, and impaired learning, thus increasing the risk of cognitive dysfunction among these individuals as compared to those with normal body mass index (BMI) values.

Neuroinflammation is another result of obesity and has been associated with both neurodegeneration and cognitive impairment. A high-fat diet has been experimentally demonstrated to produce inflammatory neuronal injury within one week of exposure, even before obesity results arise.

Obesity caused by a high-fat diet causes inflammation of the hypothalamus, the master endocrine gland. This subsequently leads to dysregulated feeding and weight gain in rodents. High fat and sugar intake also stimulate hippocampal inflammation, resulting in loss of place recognition in similar experiments.

The role of microglia in cognitive decline

Microglia are the most abundant type of brain cell associated with inflammation and the immune response. Previous studies have demonstrated that even brief periods of high-fat feeding cause gliosis in rodents, during which astrocytes and microglia proliferate to ultimately cause neuronal injury. Although initially self-resolving if the exposure is terminated, chronic exposure can lead to persistent gliosis.

As people age, cognitive impairment often develops, along with an increased risk of neurodegenerative disease due to neuroinflammation. Conversely, with increasing age, microglia are primed to respond excessively to immune stimuli, including a high fat intake by older adults.

Excessive microglia activity is associated with a specific adverse impact on cognitive function in aged individuals on a high-fat diet that is not observed in the corresponding group of young individuals. These effects could be responsible for the increased vulnerability of older adults to neurodegeneration and cognitive deficits.

The recognition of a common pathway for cognitive impairment related to both aging and obesity suggests that this neurological event could worsen with a high-fat diet in aging. However, previous studies have indicated that the obese are less likely to suffer from cognitive impairment as they age.

These contradictory findings motivated the authors of the current study to examine how microglia mediate cognitive changes in aging individuals exposed to a high-fat and high-carbohydrate diet.

What did the study show?

In the current study, female rats were fed a high-fat and high-sucrose diet (HFSD) for eight weeks, after which microglia and inflammatory markers’ expression within the brain were examined. The researchers hypothesized that aging-related cognitive impairment would be exacerbated in association with microglial changes.

To this end, accelerated weight gain in rats consuming HFSD was observed compared to those on a regular diet, with aged rats exhibiting a significant difference within two weeks compared to six weeks for young rats fed HFSD. The fat mass increase was also more significant among aged rats than among young rats; however, both groups exhibited higher fat mass by eight weeks.

Lean mass was reduced in inverse association with fat mass in both the HFSD and aged groups. Peripheral inflammation was triggered by HFSD, as demonstrated by increased cytokine interleukin 1β (IL-1β) levels; however, this effect was not observed with aging alone.

Aging was associated with increased microglia expression in the hypothalamus and hippocampus, which did not increase further when the rats were fed HFSD compared to a regular diet. Microglial complexity declined in aged rats.

The number of neuronal cells in the hippocampus was reduced in aged rats, as well as in those fed the HFSD. Neuron turnover also declined in aged rats; however, this was not observed in correlation with the HFSD. Open field exploration testing also showed a decline, with increased anxiety-like behaviors.

Recognition memory, or the ability to differentiate new from familiar objects, worsened with both aging and consumption of an HFSD; however, HFSD did not worsen the effect of aging. Interestingly, there was no evidence of a pro-inflammatory response.

These results indicate a potential disconnect between the peripheral pro-inflammatory response caused by HFSD and the central pro-inflammatory, or at least, primed, profile seen in aging.”

These observations led the scientists to selectively reduce the number of microglia in the Cx3cr1-Dtr knock-in rat model. However, there was no difference in the outcomes.

Conclusions

Our data suggest that mechanisms additional to the acute microglial contribution play a role in aging- and HFSD-associated memory dysfunction.”

Aging and HFSD may impact rat behavior by producing cognitive deficits and anxiety that do not resolve despite microglial depletion. Conversely, behavior may remain normal even while aging-related gliosis is observed in many brain regions.

Thus, microglia may not be the immediate cause of cognitive dysfunction observed with aging and HFSD over short periods. Future studies should assess the role of other pathways to understand the pathogenesis of aging-related cognitive impairment fully.

For example, the aged brain may have a pro-inflammatory environment. Furthermore, peripheral T-cells may be involved in diet-related memory loss in older adults, as depleting these cells can mitigate central neuroinflammation and prevent such impairment.

Microglial responses to poor diets like the HFSD occur acutely; therefore, microglial removal at later stages may be ineffective. It is also possible that the tests utilized in the current study were not ideal to identify the impact of such depletion on memory performance.