An Evolutionary Perspective on Why Food Overconsumption Impairs Cognition

Abstract

Brain structures and neuronal networks that mediate spatial navigation, decision-making, sociality, and creativity evolved, in part, to enable success in food acquisition. Here, I discuss evidence suggesting that the reason that overconsumption of energy-rich foods negatively impacts cognition is that signaling pathways that evolved to respond adaptively to food scarcity are relatively disengaged in the setting of continuous food availability. Obesity impairs cognition and increases the risk for some psychiatric disorders and dementias. Moreover, maternal and paternal obesity predispose offspring to poor cognitive outcomes by epigenetic molecular mechanisms. Neural signaling pathways that evolved to bolster cognition in settings of food insecurity can be stimulated by intermittent fasting and exercise to support the cognitive health of current and future generations.

Keywords: brain evolution; epigenetic modifications; hippocampus; intermittent fasting; ketogenic state; obesity; prefrontal cortex; spatial navigation.

Figure 1.. Cellular and molecular mechanisms by which food intake impacts neuroplasticity and cognition.

Left) Adaptive responses of neuronal networks to intermittent food deprivation or fasting. Extended periods with no or little energy intake triggers a metabolic shift from utilization of liver glycogen-derived glucose to adipose cell-derived fatty acids and ketone bodies (BHB, β-hydroxybutyrate; AcAc, acetoacetate) generated therefrom. In addition to serving as a source of acetyl CoA for mitochondrial ATP production, ketone bodies can activate signaling pathways involved in synaptic plasticity and cellular stress resistance, including those involving the transcription factors CREB (cyclic AMP response element binding protein) and NF-κB (nuclear factor kappa B), and neurotrophic factors such as BDNF (brain-derived neurotrophic factor). The increased activity in neuronal networks involved in cognitive processing during food seeking (navigation, decision-making, etc.) engages adaptive signaling pathways that bolster mitochondrial function and up-regulate neurotrophic factors, GABAergic tone, antioxidant defenses and DNA repair, while suppressing inflammation. These adaptive responses promote synaptic plasticity, neurogenesis and cellular stress resistance which, in turn enhances cognition and resistance of the brain to injury and disease. Right) Excessive food intake as occurs in laboratory animals fed ad libitum and most humans in modernized countries impairs neuroplasticity. Consumption of food throughout the waking hours results in little or no metabolic switching which can result in insulin resistance and a relative lack of engagement of neuronal networks involved in navigation and critical decision-making. As a consequence, signaling pathways that promote neuroplasticity and resilience are disengaged with the result being suboptimal cognitive abilities and vulnerability of the brain to stress and neurodegenerative disorders. Animal studies have shown that high energy diets and diabetes accelerate cognitive decline and motor dysfunction in models of Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. Excessive energy intake accelerates the underlying accumulation of amyloid β-peptide (Aβ) and hyperphosphorylated Tau (pTau) in the brain in AD, and α-synuclein in PD. NRF2, nuclear regulatory factor 2; PGC-1α, peroxisome proliferator-activated receptor γ coactivator 1α.

Figure 2.. Epigenetic impact of food overabundance and a sedentary lifestyle on the metabolism and cognitive outcomes of offspring.

A. Under conditions of moderate intermittent food intake and regular physical activity female mice give birth to offspring that inherit epigenetic DNA and chromatin modifications that result in gene expression profiles that promote a healthy metabolic phenotype, stress resistance, optimal cognitive function and resistance to neurological disorders. Conversely, females and males that are obese as the result of overconsumption of food and a sedentary lifestyle generate offspring that inherit epigenetic DNA and chromatin modifications and gene expression profiles that render them prone to insulin resistance and obesity, stress susceptibility, impaired cognitive function and vulnerability to neurological disorders. B. Intermittent food restriction and exercise promote epigenetic DNA and chromatin modifications (DNA and histone methylation, and chromatin protein acetylation and ubiquitination) that induce the expression of genes encoding proteins that enhance neuroplasticity and neuronal stress resistance (e.g., neurotrophic factors such as BDNF, antioxidant enzymes, protein deacetylases such as SIRT1 and SIRT3, and DNA repair enzymes such as APE1). Pro-inflammatory gene expression is suppressed by intermittent energy restriction and exercise. Food overconsumption and a sedentary lifestyle shift epigenetic modifications and consequent changes in gene expression in a manner that impairs neuroplasticity and increases vulnerability of the brain to stress. See Box 1 and references , and for details.