Ketones to the rescue of the starving fly

Abstract

Although glucose classically serves as the main neuronal fuel source in the brain, Silva et al. demonstrate that ketones produced by local glial cells are critical for memory formation in starving flies. Here we discuss the implications of these findings for aging, neurodegeneration and the genetics of ketone metabolism.

The brain is one of the largest energy consumers among organismal tissues. On average, the human brain represents only 2% of total body mass, but metabolizes about 20% of the oxygen in a resting body via oxidative phosphorylation of adenosine diphosphate (ADP) to produce ‘energy currency’in the form of adenosine triphosphate (ATP)¹. The majority of the energy is consumed by the brain during neuronal signaling². Glucose serves as the main fuel source for energy metabolism and is also required for neurotransmitter synthesis and cell maintenance in the brain³. Energy metabolism in a neuron is integrally connected to supporting cells such as astrocytes. Uptake of glutamate, an excitatory neurotransmitter released from synapses, triggers the use of glucose and production of lactate in astrocytes⁴. Importantly, glucose can be stored as glycogen in astrocytes and can potentially be converted into pyruvate, lactate and glucose for energy metabolism or can be used for glutamate synthesis. The astrocyte-derived lactate or glucose can be transported and used by the neurons as well through the astrocyte–neuronl actate shuttle⁵. Lactate is transported between astrocytes and neurons by monocarboxylate transporters, and this transport is important for long-term memory formation⁵. Energy deprivation in the brain disrupts ion homeostasis and can lead to excitotoxicity due to overactivation caused by neurotransmitters such as glutamate⁶. Therefore, energy metabolism needs to be tightly regulated. The study by Silva et al. investigated the role of ketone bodies as an alternative source of energy in the brain to sustain memory formation under glucose-deprived conditions⁷.

Silva et al. first showed the effects of starvation on memory in flies and demonstrated that improved cognitive performance relies on ketone body metabolism. These results confirm previous reports that show that ketone bodies play an important role in the maintenance of neuronal systems under reduced nutrient intake in mammals⁸ and demonstrate that this effect is conserved in flies. Second, they showed that cortex glia are responsible for fatty acid metabolism, which generates these crucial ketone bodies, thus highlighting the relevance of these cells for providing energy to neurons in the brain. Third, through cell-specific genetic alterations, they identified the monocarboxylate transporters in flies that are required for transporting ketone bodies to neurons, again demonstrating the conserved factors that regulate this effect. Finally, they showed that AMP-activated protein kinase (AMPK) is the key regulator of this process. In short, this study elegantly demonstrates a metabolic switch during starvation in which an organism uses ketone bodies as an alternate fuel source to sustain memory formation⁷. The authors not only identify the key players in Drosophila for regulating memory under starvation, but also provide evidence of the evolutionary conservation of ketogenesis and ketone transport in this model. Ketogenic diets are mostly studied as dietary interventions for improving metabolic health, but the role they might play in supporting cognitive processes provides a fresh view on their potential therapeutic applications.

Importantly, the findings by Silva et al. will help to expedite studies of ketones in enhancing health and longevity. Most studies to date have relied on the use of mammalian models, which are costlier and more time-consuming. Conservation of these mechanisms in flies will allow more rapid genetic analysis, which can be used to test factors that will affect regulators of ketone body production and use. This report opens a new avenue to investigate the restoration of energy homeostasis in diseased and aged brains by mobilizing alternative energy sources. Hypometabolism of glucose in the brain is well-established in age-related dementias⁹. Furthermore, a decline in ATP has also been demonstrated with age and certain neurodegenerative disorders¹⁰. As suggested by Silva et al. and others, starvation-induced ketone signaling to the brain can be beneficial⁸, and thus an important future direction is understanding how ketone bodies could be used to treat or prevent age-related neurodegenerative diseases.

Exogenous ketone feeding, as well as ketogenic diets, have been implicated as possible routes for improving lifespan and healthspan¹¹. A natural follow-up analysis to the study by Silva et al. would be to test how exogenous ketone feeding can be used to combat aging and age-related memory impairment. As flies possess an open circulatory system (not enclosed by blood vessels), the utilization of ketones in the body could be accelerated via circulation in the hemolymph, which will be useful for studying how circulating ketones can be used as a therapeutic approach for age-related cognitive decline.

Ketones can also induce changes in gene expression¹². Thus, understanding changes in the transcriptome that are caused by changes in ketone metabolism will also be important in dissecting the downstream mechanisms of ketones in addition to their role in providing ATP. An issue, however, is that additional genetic factors can influence ketone metabolism, thus complicating how they would affect individuals. Our previous work in flies has shown that genetic variation can alter the endogenous levels of the ketone bodies acetoacetic acid and 3-hydroxybutyrate, including in response to dietary restriction¹³. Additional previous work in flies has shown that glial cells are responsible for breaking down fatty acids that are transported out of neurons, a process that generates lactate, which is then shuttled back to the neurons as a source of energy¹⁴. The same group also showed that different alleles of APOE can impact this process, with APOE4 being the less-effective lipid transporter and contributing to Alzheimer’s-associated lipid build-up¹⁵. An important study would be to analyze how this and other neurodegenerative biomarkers affect ketogenesis and memory.

Overall, there are several factors that need to be studied further to improve our understanding of how ketones can be used to combat aging and age-related diseases (Fig. 1). Silva et al. have demonstrated that ketones are an alternative energy substrate that can preserve brain function during starvation, while also showing that flies are a legitimate tool to study ketone metabolism and its relevance to human health.

Fig. 1 |. Starvation induces a metabolic shift, which is conserved in flies, to elevate ketone body production and improve memory.

The proteins involved in this process include: AMPK, which serves as the master regulator; HMGS, CPT1 and Bmm, which break down lipids for ketone body production; Chk and Sln, which transport ketones from the glia to neurons; and ACAT1, which utilizes the ketones to generate energy. These findings raise the questions of how ketogenesis can influence aging and neurodegenerative diseases, and which other genes might influence this process.