A Walnut Diet\xa0in Combination with Enriched Environment Improves\xa0Cognitive Function and Affects Lipid Metabolites in Brain and Liver of Aged NMRI Mice

Carsten Esselun,Elisabeth Koch,Gunter P. Eckert,Benjamin Dilberger,Nils Helge Schebb,Carmina V. Silaidos

doi:10.1007/s12017-020-08639-7

Carsten Esselun, Elisabeth Koch + Show 4 more

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https://doi.org/10.1007/s12017-020-08639-7

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Abstract

This in vivo study aimed to test if a diet enriched with 6% walnuts alone or in combination with physical activity supports healthy ageing by changing the oxylipin profile in brain and liver, improving motor function, cognition, and cerebral mitochondrial function. Female NMRI mice were fed a 6% walnut diet starting at an age of 12 months for 24 weeks. One group was additionally maintained in an enriched environment, one group without intervention served as control. After three months, one additional control group of young mice (3 weeks old) was introduced. Motor and cognitive functions were measured using Open Field, Y-Maze, Rotarod and Passive Avoidance tests. Lipid metabolite profiles were determined using RP-LC-ESI(-)-MS/MS in brain and liver tissues of mice. Cerebral mitochondrial function was characterized by the determination of ATP levels, mitochondrial membrane potential and mitochondrial respiration. Expression of genes involved with mito- and neurogenesis, inflammation, and synaptic plasticity were determined using qRT-PCR. A 6% walnut-enriched diet alone improved spatial memory in a Y-Maze alternation test (p < 0.05) in mice. Additional physical enrichment enhanced the significance, although the overall benefit was virtually identical. Instead, physical enrichment improved motor performance in a Rotarod experiment (p* < 0.05) which was unaffected by walnuts alone. Bioactive oxylipins like hydroxy-polyunsaturated fatty acids (OH-PUFA) derived from linoleic acid (LA) were significantly increased in brain (p** < 0.01) and liver (p*** < 0.0001) compared to control mice, while OH-PUFA of α-linolenic acid (ALA) could only be detected in the brains of mice fed with walnuts. In the brain, walnuts combined with physical activity reduced arachidonic acid (ARA)-based oxylipin levels (p < 0.05). Effects of walnut lipids were not linked to mitochondrial function, as ATP production, mitochondrial membrane potential and mitochondrial respiration were unaffected. Furthermore, common markers for synaptic plasticity and neuronal growth, key genes in the regulation of cytoprotective response to oxidative stress and neuronal growth were unaffected. Taken together, walnuts change the oxylipin profile in liver and brain, which could have beneficial effects for healthy ageing, an effect that can be further enhanced with an active lifestyle. Further studies may focus on specific nutrient lipids that potentially provide preventive effects in the brain.

Highlights

In physiological ageing as well as in neurodegenerative diseases like Alzheimer’s disease (AD) or Parkinson’s disease, mitochondrial dysfunction (Swerdlow et al 2014) and chronic inflammation (Minciullo et al 2016) appear to play key roles in cognitive decline and decreased motor function
Oxylipin Profile and Gene Expression in the Liver As our data suggest that neither gene expression in the brain nor mitochondrial function were affected by the intervention diet, we looked at whether the diet was affecting fatty acid metabolism
Parameters for the statistical tests can be found in the supplementary Table S2 diets might have an effect on inflammatory processes, commonly increasing during the process of ageing, we explored the free, i.e. nonesterified oxylipin profiles in brain and liver tissue

Summary

Introduction

In physiological ageing as well as in neurodegenerative diseases like Alzheimer’s disease (AD) or Parkinson’s disease, mitochondrial dysfunction (Swerdlow et al 2014) and chronic inflammation (Minciullo et al 2016) appear to play key roles in cognitive decline and decreased motor function. Low-grade chronic, systemic inflammation during ageing, often referred to as “inflammaging”, is based on the body’s decreasing ability to ameliorate inflammatory events, leading to an increased production of pro-inflammatory cytokines like IL1β or TNF1α or prostaglandins such as PGE2 or thromboxanes (Minciullo et al 2016; Neves and Sousa-Victor 2019). The same enzymes oxidize n3-fatty acids like α-linolenic acid (ALA), eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). Most of these metabolites are widely considered to exhibit antiinflammatory effects (Nayeem 2018). N6- and n3-fatty acids (Kutzner et al 2017) compete as substrates for COX, LOX and CYP, dietary supplementation with specific fatty acids is suspected to modify the metabolite profile in the body (Nayeem 2018; Ostermann et al 2017a)

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