Ketosis Elevates Antioxidants and Markers of Energy Metabolism: A Proton Magnetic Resonance Spectroscopy Study

Background: Ketosis is known to alter the balance of neuroactive amino acids and enhance neural function compared with a glycolytic condition. However, its influence on other metabolites, such as antioxidants and neural energy markers, and the mechanisms by which ketosis improves neural function remain unclear. Methods: Here, we measured the neurochemical effects of acute ketosis on key brain metabolites (neurotransmitters, antioxidants, and energy markers) in the human brain using ultra-high-field proton magnetic resonance spectroscopy (¹H-MRS) and investigated the subsequent impact on neural function, measured via dynamic functional connectivity, using resting-state functional magnetic resonance imaging (rs-fMRI). In a within-subjects design, 63 healthy adults (30 female) from across the lifespan underwent¹H-MRS and rs-fMRI scans before and after consuming individually weight-dosed and calorically matched ketone monoester or glucose drinks. Results: Ketone monoester administration, but not glucose, significantly elevated cerebral antioxidants and energy markers while decreasing GABA (gamma-aminobutyric acid), glutamate, and glutamine levels in the posterior cingulate cortex. Notably, increased energy markers, specifically an increase in total creatine, correlated with greater improvements in neural function measured using rs-fMRI. Conclusions: Our results integrate metabolic and functional neuroimaging findings, offering a comprehensive understanding of ketosis-induced changes in brain chemistry and functional network dynamics. These insights clarify potential mechanisms by which ketosis imparts its neural benefits and provide valuable information to assist the development of novel treatment strategies for a variety of psychiatric and neurodegenerative disorders.