Regular articleHigh-fat diet and aging interact to produce neuroinflammation and impair hippocampal- and amygdalar-dependent memory
Introduction
In the last 100 years, diet in developed countries has seen astounding increases in the amounts of fats and sugar consumed (Guyenet and Carlson, 2015, Putnam and Allshouse, 1999). Not surprisingly, these increases are correlated with rising obesity rates. Approximately, 40% of the adult U.S. population is currently obese, a dramatic increase from the 13% incidence of 1960 (Fryar et al., 2016, Ogden et al., 2015). Importantly, the prevalence among older individuals (aged 60–74) has nearly doubled since just 1980 (Fakhouri et al., 2012), and with the population of Americans over the age of 65 expected to reach 25% by the year 2030 (Alzheimer's Association, 2016, Wimo et al., 2013), any health risks associated with aging and unhealthy diets are likely to become even greater in the future.
Aging is a major risk factor for inflammation-induced mild cognitive impairments, as demonstrated in both the clinical and preclinical literature (Alzheimer's Association, 2016, Barrientos et al., 2015, Corona et al., 2012, Holmes et al., 2003, Moller et al., 1998, Murray et al., 2012). Importantly, mild cognitive impairments among older individuals increase the probability for developing Alzheimer's disease later in life (Alzheimer's Association, 2016, Miller and Spencer, 2014). As many have shown, microglia, the brain's resident immune cells, become sensitized with age, lowering their threshold for activation (Frank et al., 2006, Frank et al., 2010b, Perry et al., 1993, Rogers et al., 1988, Rozovsky et al., 1998). When either a peripheral or central inflammatory challenge is experienced, these sensitized microglia become hyperactivated and produce pathologic levels of proinflammatory cytokines, thereby interfering with synaptic plasticity processes, potentially resulting in precipitous memory declines (Chapman et al., 2010, Chapman et al., 2012, Combrinck et al., 2002, Cunningham et al., 2009). Previous research has demonstrated that this sequence occurs in aged rodents in response to bacterial and viral infections, and surgical insults (Abraham et al., 2008, Barrientos et al., 2006, Barrientos et al., 2012, Chen et al., 2008, Rosczyk et al., 2008). We hypothesize that acute high-fat diet (HFD), such as occurs with binge-eating and fast-food meals, may be an important pathologic trigger, similar to infection or surgery, to induce overt brain inflammation and memory loss in the already-sensitized aging brain.
While HFD in young adults produces low-grade inflammation in the circulation and peripheral tissues (Cano et al., 2009, Coppack, 2001, Xu et al., 2002), its ability to directly induce inflammation within the brain is limited to the hypothalamus (De Luca et al., 2016, Maric et al., 2014, Milanski et al., 2009), except after extremely long-term HFD during which diabetes-like symptoms are starting to occur (Jeon et al., 2012). In the hippocampus, HFD in the young adult is not directly inflammatory and only sensitizes cells to over-respond to future inflammatory stimuli (Sobesky et al., 2014, Sobesky et al., 2016). In the absence of such stimuli, no inflammatory response is detected nor memory impairments observed. Interestingly, even as little as 3 days, HFD is sufficient to sensitize the hippocampus in this way (Sobesky et al., 2014, Sobesky et al., 2016). Despite these pronounced effects of short-term HFD on extra-hypothalamic regions of the brain in the young adult, the inflammatory effect of HFD in the already-vulnerable aging brain has not yet been assessed. Here, we hypothesized that consumption of a HFD would serve as a neuroinflammatory trigger in aging animals, leading to cognitive deficits, without having an overt proinflammatory or cognitive effect in young adults.
Section snippets
Subjects
Subjects were male F344×BN F1 rats obtained from the National Institute on Aging Rodent Colony maintained by Envigo (Indianapolis, IN, USA). On arrival at our facility, aged rats were 24 months old and weighed approximately 500 g. Young adult rats were 3 months old and weighed approximately 300 g. Following arrival, animals were allowed to acclimate to the facility for at least 7 days before diet modifications. With the exception of the exercise experiments, where they were individually housed,
3 Days HFD increases body mass, particularly in aged rats
Young and aged rats were weighed on the day of their introduction to the HFD (day 0) and every day for 3 days. As expected, the body weight averages for aged rats at the start of the experiment were significantly greater than those of young rats (F(1,36) = 198.6, p < 0.0001 Fig. 1, inset; n = 10 for each group). With regard to percent change in body weight over the 3 days, a significant interaction effect of age × diet (F(1,2) = 32.98, p < 0.0001) and day × diet (F(2,2) = 23.41, p < 0.0001)
Discussion
Together, these findings suggest that aged rats are particularly vulnerable to contextual and cued fear memory disruptions following short-term consumption of an HFD. That is, HFD appears to affect both hippocampal and amygdalar functioning. A previous study demonstrated long-term HFD-induced impairments of hippocampal spatial memory in aged rats. In this study, 14-month-old F344 rats that were fed a 36% fat diet supplemented with 10% coconut oil and 2% cholesterol for 6 months were impaired on
Disclosure statement
The authors have no conflicts of interest to disclose.
Acknowledgements
This work was supported by grants from the National Institute on Aging R01AG028271 to LRW, SFM, and RMB and by an Australian Research Council Future Fellowship (FT110100084), an RMIT University Vice Chancellor's Senior Research Fellowship, and a Club Melbourne Fellowship to SJS.
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