Brain metabolism in health, aging, and neurodegeneration

Abstract

Brain cells normally respond adaptively to bioenergetic challenges resulting from ongoing activity in neuronal circuits, and from environmental energetic stressors such as food deprivation and physical exertion. At the cellular level, such adaptive responses include the "strengthening" of existing synapses, the formation of new synapses, and the production of new neurons from stem cells. At the molecular level, bioenergetic challenges result in the activation of transcription factors that induce the expression of proteins that bolster the resistance of neurons to the kinds of metabolic, oxidative, excitotoxic, and proteotoxic stresses involved in the pathogenesis of brain disorders including stroke, and Alzheimer's and Parkinson's diseases. Emerging findings suggest that lifestyles that include intermittent bioenergetic challenges, most notably exercise and dietary energy restriction, can increase the likelihood that the brain will function optimally and in the absence of disease throughout life. Here, we provide an overview of cellular and molecular mechanisms that regulate brain energy metabolism, how such mechanisms are altered during aging and in neurodegenerative disorders, and the potential applications to brain health and disease of interventions that engage pathways involved in neuronal adaptations to metabolic stress.

Intermittent metabolic switching, neuroplasticity and brain health

“…Every time they eat, the glycogen stores in their liver are replenished; liver glycogen provides 700–900 calories of glucose or energy, an amount that will last 10–14 hours in individuals who are not exercising. Subsequently, liver energy stores are depleted, circulating glucose levels remain low and adipose cells release fatty acids, which are converted in the liver to the ketone bodies β-hydroxybutyrate (BHB) and acetoacetate (AcAc), which are released into the blood and are used as energy substrates by neurons 4,5 (FIG. 1).…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…Astrocytes may also contribute to adaptive responses to age-related neuronal stress. They produce neurotrophic factors, remove glutamate from synapses, and bolster neuronal bioenergetics (Mattson and Rychlik, 1990; Camandola and Mattson, 2017; Rose et al, 2018). These functions of astrocytes may be compromised during aging, thereby exacerbating pathological neuroinflammatory processes.…”

“…Previous review articles provide comprehensive descriptions of alterations in brain cellular metabolism that occur in aging and their interface with neurodegenerative disorders (Kapogiannis and Mattson, 2011; Ryan et al, 2015; Yin et al, 2016; Swerdlow, 2016; Camandola and Mattson, 2017). PET imaging studies reveal impaired cerebral glucose utilization occurring very early in AD pathogenesis, even before overt clinical symptoms are evident (Friedland et al, 1989; Ceravolo et al, 2008).…”

Insulin and the Brain

“…Neurons predominantly have an oxidative metabolism, whereas astrocytes are largely glycolic [4]. Following cytosolic reactions, energy fuels are mainly metabolised in the mitochondria.…”

“…Thus, misappropriation of glucose utilization exclusively to glycolysis may result in decreased NADPH availability, increased oxidative stress and cell death. Though negligible compared to peripheral energy deposits, glycogen is the largest energy reserve in the brain [4]. Astrocyte use of glucose is complementary to that of neurons.…”