Ketosis elevates antioxidants and markers of energy metabolism: A H MR spectroscopy study.

Background: Ketosis is known to alter the balance of neuroactive amino acids and enhance neural function when compared to 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 measure the neurochemical effects of acute ketosis on key brain metabolites (neurotransmitters, antioxidants, and energy markers) in the human brain using ultra-high-field H MR spectroscopy (MRS) and investigate the subsequent impact on neural function, measured via dynamic functional connectivity, using resting-state functional magnetic resonance imaging (rsfMRI).

Brain aging shows nonlinear transitions, suggesting a midlife "critical window" for metabolic intervention.

Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal "landmarks" of brain aging starting in midlife (40s).

Ketosis regulates K ion channels, strengthening brain-wide signaling disrupted by age.

Aging is associated with impaired signaling between brain regions when measured using resting-state fMRI. This age-related destabilization and desynchronization of brain networks reverses itself when the brain switches from metabolizing glucose to ketones. Here, we probe the mechanistic basis for these effects.

Ketone Esters Partially and Selectively Rescue Mitochondrial Bioenergetics After Acute Cervical Spinal Cord Injury in Rats: A Time-Course.

Spinal cord injury (SCI) pathology and pathophysiology can be attributed to both primary physical injury and secondary injury cascades. Secondary injury cascades involve dysregulated metabolism and energetic deficits directly linked to compromised mitochondrial bioenergetics. Rescuing mitochondrial function and reducing oxidative stress are associated with neuroprotection.

The age-dependent development of abnormal cardiac metabolism in the peroxisome proliferator-activated receptor α-knockout mouse.

Background And Aims: Peroxisome proliferator-activated receptor α (PPARα) is crucial for regulating cardiac β-oxidation in the heart, liver, and kidney. Ageing can induce cardiac metabolic alterations, but the role of PPARα has not been extensively characterised. The aim of this research was to investigate the role of PPARα in the aged heart.

Hyperpolarized C and P MRS detects differences in cardiac energetics, metabolism, and function in obesity, and responses following treatment.

Obesity is associated with important changes in cardiac energetics and function, and an increased risk of adverse cardiovascular outcomes. Multi-nuclear MRS and MRI techniques have the potential to provide a comprehensive non-invasive assessment of cardiac metabolic perturbation in obesity. A rat model of obesity was created by high-fat diet feeding.

On the interdependence of ketone body oxidation, glycogen content, glycolysis and energy metabolism in the heart.

In heart, glucose and glycolysis are important for anaplerosis and potentially therefore for d-β-hydroxybutyrate (βHB) oxidation. As a glucose store, glycogen may also furnish anaplerosis. We determined the effects of glycogen content on βHB oxidation and glycolytic rates, and their downstream effects on energetics, in the isolated rat heart.

Evaluation of Acute Supplementation With the Ketone Ester ()-3-Hydroxybutyl-(R)-3-Hydroxybutyrate (deltaG) in Healthy Volunteers by Cardiac and Skeletal Muscle P Magnetic Resonance Spectroscopy.

In this acute intervention study, we investigated the potential benefit of ketone supplementation in humans by studying cardiac phosphocreatine to adenosine-triphosphate ratios (PCr/ATP) and skeletal muscle PCr recovery using phosphorus magnetic resonance spectroscopy (P-MRS) before and after ingestion of a ketone ester drink. We recruited 28 healthy individuals: 12 aged 23-70 years for cardiac P-MRS, and 16 aged 60-75 years for skeletal muscle P-MRS. Baseline and post-intervention resting cardiac and dynamic skeletal muscle P-MRS scans were performed in one visit, where 25 g of the ketone monoester, deltaG, was administered after the baseline scan.

Abnormal whole-body energy metabolism in iron-deficient humans despite preserved skeletal muscle oxidative phosphorylation.

Iron deficiency impairs skeletal muscle metabolism. The underlying mechanisms are incompletely characterised, but animal and human experiments suggest the involvement of signalling pathways co-dependent upon oxygen and iron availability, including the pathway associated with hypoxia-inducible factor (HIF). We performed a prospective, case-control, clinical physiology study to explore the effects of iron deficiency on human metabolism, using exercise as a stressor.

Exogenous d-β-hydroxybutyrate lowers blood glucose in part by decreasing the availability of L-alanine for gluconeogenesis.

Background: Interventions that induce ketosis simultaneously lower blood glucose and the explanation for this phenomenon is unknown. Additionally, the glucose-lowering effect of acute ketosis is greater in people with type 2 diabetes (T2D). On the contrary, L-alanine is a gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D and infusing of ketones lower circulating L-alanine blood levels.

Metabolic maturation of differentiating cardiosphere-derived cells.

Cardiosphere-derived cells (CDCs) can be expanded in vitro and induced to differentiate along the cardiac lineage. To recapitulate the phenotype of an adult cardiomyocyte, differentiating progenitors need to upregulate mitochondrial glucose and fatty acid oxidation. Here we cultured and differentiated CDCs using protocols aimed to maintain stemness or to promote differentiation, including triggering fatty acid oxidation using an agonist of peroxisome proliferator-activated receptor alpha (PPARα).

The Use of Reactive Oxygen Species Production by Succinate-Driven Reverse Electron Flow as an Index of Complex 1 Activity in Isolated Brown Adipose Tissue Mitochondria.

We compared the activity of complex 1, complex 2, and the expression of the complex 1 subunit, NDUFA9, in isolated brown adipose tissue mitochondria from wild type and mitochondrial uncoupling protein 1 (UCP1) knockout mice. Direct spectrophotometric measurement revealed that complex 2 activity was similar, but complex 1 activity was greater (~2.7 fold) in isolated mitochondria from wild-type mice compared to UCP1 knockout mice, an observation endorsed by greater complex 1 subunit expression (NDUFA9) in mitochondria of wild-type mice.

Effects of acute nutritional ketosis during exercise in adults with glycogen storage disease type IIIa are phenotype-specific: An investigator-initiated, randomized, crossover study.

Glycogen storage disease type IIIa (GSDIIIa) is an inborn error of carbohydrate metabolism caused by a debranching enzyme deficiency. A subgroup of GSDIIIa patients develops severe myopathy. The purpose of this study was to investigate whether acute nutritional ketosis (ANK) in response to ketone-ester (KE) ingestion is effective to deliver oxidative substrate to exercising muscle in GSDIIIa patients.

The ketone ester, 3-hydroxybutyl-3-hydroxybutyrate, attenuates neurobehavioral deficits and improves neuropathology following controlled cortical impact in male rats.

Traumatic brain injury (TBI) is a leading cause of human death and disability with no effective therapy to fully prevent long-term neurological deficits in surviving patients. Ketone ester supplementation is protective in animal models of neurodegeneration, but its efficacy against TBI pathophysiology is unknown. Here, we assessed the neuroprotective effect of the ketone monoester, 3-hydroxybutyl-3-hydroxybutyrate, (KE) in male Sprague Dawley rats (=32).

A Ketone Ester Drink Enhances Endurance Exercise Performance in Parkinson's Disease.

Objectives: Routine exercise is thought to be among the only disease-modifying treatments for Parkinson's disease; however, patients' progressive loss of physical ability limits its application. Therefore, we sought to investigate whether a ketone ester drink, which has previously been shown to enhance endurance exercise performance in elite athletes, could also improve performance in persons with Parkinson's disease.

Participants: 14 patients, aged 40-80 years, with Hoehn and Yahr stage 1-2 Parkinson's disease.

Nicotinic acid receptor agonists impair myocardial contractility by energy starvation.

Nicotinic acid receptor agonists have previously been shown to cause acute reductions in cardiac contractility. We sought to uncover the changes in cardiac metabolism underlying these alterations in function. In nine humans, we recorded cardiac energetics and function before and after a single oral dose of nicotinic acid using cardiac MRI to demonstrate contractile function and Phosphorus-31 ( P) magnetic resonance spectroscopy to demonstrate myocardial energetics.

The Effect of Blood Ketone Concentration and Exercise Intensity on Exogenous Ketone Oxidation Rates in Athletes.

Introduction: Exogenous ketones potentially provide an alternative, energetically advantageous fuel to power exercising skeletal muscle. However, there is limited evidence regarding their relative contribution to energy expenditure during exercise. Furthermore, the effect of blood ketone concentration and exercise intensity on exogenous ketone oxidation rates is unknown.

Ketotherapeutics for neurodegenerative diseases.

Alzheimer's disease (AD) and Parkinson's disease (PD) are, respectively, the most prevalent and fastest growing neurodegenerative diseases worldwide. The former is primarily characterized by memory loss and the latter by the motor symptoms of tremor and bradykinesia. Both AD and PD are progressive diseases that share several key underlying mitochondrial, inflammatory, and other metabolic pathologies.

Male sex adversely affects the phenotypic expression of diabetic heart disease.

Background: Type 2 diabetes (T2D) is associated with an increased risk of heart failure (HF) and cardiovascular mortality. A large-scale meta-analysis on HF found that diabetes was more frequent in women than men, and diabetes appeared to have attenuated the otherwise protective effect of female sex on progression of cardiomyopathy. The exact underlying mechanisms for this remain unclear.

Diet modulates brain network stability, a biomarker for brain aging, in young adults.

Epidemiological studies suggest that insulin resistance accelerates progression of age-based cognitive impairment, which neuroimaging has linked to brain glucose hypometabolism. As cellular inputs, ketones increase Gibbs free energy change for ATP by 27% compared to glucose. Here we test whether dietary changes are capable of modulating sustained functional communication between brain regions (network stability) by changing their predominant dietary fuel from glucose to ketones.

Why a d-β-hydroxybutyrate monoester?

Much of the world's prominent and burdensome chronic diseases, such as diabetes, Alzheimer's, and heart disease, are caused by impaired metabolism. By acting as both an efficient fuel and a powerful signalling molecule, the natural ketone body, d-β-hydroxybutyrate (βHB), may help circumvent the metabolic malfunctions that aggravate some diseases. Historically, dietary interventions that elevate βHB production by the liver, such as high-fat diets and partial starvation, have been used to treat chronic disease with varying degrees of success, owing to the potential downsides of such diets.