Glucose and Ketone Metabolism in the Aging Brain

2016 ◽  
Author(s):  
Stephen C. Cunnane ◽  
Alexandre Courchesne-Loyer ◽  
Valerie St-Pierre ◽  
Camille Vandenberghe ◽  
Etienne Croteau ◽  
...  
Keyword(s):  
Alternative Fuels ◽  
Ketone Bodies ◽  
Therapeutic Strategies ◽  
Cognitive Outcomes ◽  
Aging Brain ◽  
High Fat ◽  
Medium Chain Triglycerides ◽  
Acute Dependence ◽  
Beta Hydroxybutyrate ◽  
The Brain

Brain glucose uptake is impaired in Alzheimer’s disease (AD). A key question is whether cognitive decline could be delayed if this defect were at least partly corrected or bypassed. Ketones (or ketone bodies) such as beta-hydroxybutyrate and acetoacetate are the brain’s main alternative fuels. Several studies have shown that in mild-to-moderate AD, brain ketone uptake is similar to that of healthy age-matched controls. Published clinical trials show that increasing ketone availability to the brain via nutritional ketosis has modest benefits on cognitive outcomes in mild-to-moderate AD and in mild cognitive impairment. Nutritional ketosis can be safely achieved by a high-fat ketogenic diet or supplements providing medium chain triglycerides. Given the acute dependence of the brain on its energy supply and the ineffectiveness of current therapeutic strategies for AD consideration be given to correcting the underlying problem of deteriorating brain fuel supply during aging.

scholarly journals Exploring the Viability of Exogenous Ketones as Weight Loss Supplements (P21-017-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Angela Poff ◽  
Andrew Koutnik ◽  
Sara Moss ◽  
Sahith Mandala ◽  
Dominic D'Agostino
Keyword(s):  
Weight Loss ◽  
Caloric Restriction ◽  
Ketone Bodies ◽  
Standard Diet ◽  
Medium Chain Triglycerides ◽  
Future Studies ◽  
Medium Chain ◽  
Funding Sources ◽  
Beta Hydroxybutyrate ◽  
Main Strategy

Abstract Objectives 70.7% of Americans over 20 years of age are overweight or obese. Currently, the main strategy for weight loss is caloric restriction. Ketone bodies have been shown to facilitate voluntary caloric restriction through altering the appetite stimulating hormone ghrelin. However, these non-toxic ketone bodies have not been evaluated as weight loss supplements. C57BL6J mice were used to determine the weight loss efficacy of exogenous ketones by adding synthetic (R/S 1,3-Butanediol Acetoacetate Diester and 1,3-Butanediol) and natural (Beta-hydroxybutyrate and Beta-hydroxybutyrate + Medium Chain Triglycerides) ketogenic agents to standard rodent chow ab-libitum. Methods Six groups (R/S 1,3-butanediol acetoacetate diester, 1,3-butanediol, beta-hydroxybutyrate, beta-hydroxybutyrate + medium chain triglycerides, caloric restriction, standard diet ad-libitum) were housed 2–5 animals per cage and monitored to ensure appropriate acclimation prior to intervention. Mice were treated for two weeks with ketogenic agents, adjusting % of agent daily to ensure 20% weight loss was achieved. Results All ketogenic agents induced weight loss and voluntary caloric restriction. Weight loss for beta-hydroxybutyrate and beta-hydroxybutyrate + medium chain triglycerides was explained by caloric restriction alone. However, R/S 1,3-butanediol acetoacetate diester induced weight loss at lower dosages which could not be explained by caloric restriction alone. Conclusions Taken together, all ketogenic agents may assist in weight loss. However, R/S 1,3-butanediol acetoacetate diester appears to be a more potent non-toxic ketogenic supplement that facilitates weight loss via both voluntary caloric restriction and caloric restriction-independent mechanisms. Future studies should explore caloric-restriction independent weight loss mechanisms of R/S 1,3-butanediol acetoacetate diester. Funding Sources Disruptive Nutrition.

scholarly journals An fMRI Investigation into the Effects of Ketogenic Medium-Chain Triglycerides on Cognitive Function in Elderly Adults: A Pilot Study

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2134
Author(s):  
Yukihito Yomogida ◽  
Junko Matsuo ◽  
Ikki Ishida ◽  
Miho Ota ◽  
Kentaro Nakamura ◽  
...  
Keyword(s):  
Energy Source ◽  
Cognitive Function ◽  
Task Performance ◽  
Ketone Bodies ◽  
Elderly Subjects ◽  
Medium Chain Triglycerides ◽  
Medium Chain ◽  
Extra Energy ◽  
The Brain ◽  
Back Task

Evidence suggests that oral intake of medium-chain triglycerides (MCTs), which promote the production of ketone bodies, may improve cognitive functions in elderly people; however, the underlying brain mechanisms remain elusive. We tested the hypothesis that cognitive improvement accompanies physiological changes in the brain and reflects the use of ketone bodies as an extra energy source. To this end, by using functional magnetic resonance imaging, cerebral blood oxygenation level-dependent (BOLD) signals were measured while 20 healthy elderly subjects (14 females and 6 males; mean age: 65.7 ± 3.9 years) were engaged in executive function tasks (N-back and Go-Nogo) after ingesting a single MCT meal (Ketonformula®) or placebo meal in a randomized, double-blind placebo-controlled design (UMIN000031539). Morphological characteristics of the brain were also examined in relation to the effects of an MCT meal. The MCT meal improved N-back task performance, and this was prominent in subjects who had reduced grey matter volume in the dorsolateral prefrontal cortex (DLPFC), a region known to promote executive functions. When the participants were dichotomized into high/low level groups of global cognitive function at baseline, the high group showed improved N-back task performance, while the low group showed improved Go-Nogo task performance. This was accompanied by decreased BOLD signals in the DLPFC, indicative of the consumption of ketone bodies as an extra energy source.

Effects of D-beta-hydroxybutyrate and long- and medium-chain triglycerides on leucine metabolism in humans

1992 ◽  
Vol 262 (3) ◽  
pp. E268-E274 ◽  
Author(s):  
B. Beaufrere ◽  
D. Chassard ◽  
C. Broussolle ◽  
J. P. Riou ◽  
M. Beylot
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Parenteral Nutrition ◽  
Ketone Bodies ◽  
Medium Chain Triglycerides ◽  
Medium Chain ◽  
Leucine Metabolism ◽  
Protein Sparing ◽  
Beta Hydroxybutyrate ◽  
Long Chain

Ketone bodies and/or fatty acids might play a protein-sparing role during prolonged fasting or parenteral nutrition. To assess this problem, we studied whole body leucine metabolism, using L-[1-13C]leucine in normal postabsorptive volunteers who received either long-chain triglycerides (LCT, 0.15 g.kg-1.h-1, 6 subjects), a 50-50 mixture of medium-chain triglycerides (MCT) and LCT (0.15 g.kg-1.h-1, 6 subjects), D-beta-hydroxybutyrate (540 mumol.kg-1.h-1, 6 subjects), or saline (4 subjects). Leucine concentration decreased only with MCT-LCT. Leucine flux decreased by 10-20% from basal in all groups. Leucine oxidation, which was corrected for the contribution to 13CO2 of the 13C natural abundance of the infused substrates, decreased during LCT infusion (0.31 +/- 0.02 to 0.24 +/- 0.01 mumol.kg-1.min-1, P less than 0.01), but was unaffected by MCT-LCT (despite plasma free fatty acid levels similar to those obtained with LCT), D-beta-hydroxybutyrate, or saline infusion. Therefore, 1) the effect of fatty acids on amino acid oxidation is not mediated by ketone bodies, 2) it depends on the fatty acid chain length, 3) long-chain fatty acids but not medium-chain fatty acids could play a protein-sparing role during parenteral nutrition.

Regional ketone body utilization by rat brain in starvation and diabetes

1986 ◽  
Vol 250 (2) ◽  
pp. E169-E178 ◽  
Author(s):  
R. A. Hawkins ◽  
A. M. Mans ◽  
D. W. Davis
Keyword(s):  
Energy Metabolism ◽  
Plasma Clearance ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Energy Requirement ◽  
Diabetic Rats ◽  
Beta Hydroxybutyrate ◽  
The Brain ◽  
Brain Energy ◽  
Cerebral Structures

The rate of ketone body (beta-hydroxybutyrate and acetoacetate) metabolism was measured in individual cerebral structures of fed, starved, and diabetic rats. This was done by infusing beta-[3-14C]hydroxybutyrate intravenously and measuring the incorporation of 14C into brain by quantitative autoradiography. The capacity of the brain to use ketone bodies, expressed as plasma clearance, increased in starvation and diabetes by approximately 50-60%. Plasma clearance was near maximal after 2 days starvation and was not significantly increased after 4 days starvation, 6 days of diabetes or 28 days of diabetes. In all situations the ketone bodies provided only a modest amount of fuel for brain energy metabolism; 3.2% after 2 days starvation and 6.5 and 9.9% after 6 and 28 days of diabetes. The fraction of their energy requirement which the various structures could derive from the ketone bodies differed widely. In general the telencephalon made greatest use of ketone bodies, whereas the hindbrain used least. There was no correlation between the energy requirement of structures (estimated from glucose use in fed rats) and the fraction of energy they could derive from ketone bodies.

Overview of Ketone-Based Metabolism

2016 ◽  
Author(s):  
Dominic P. D’Agostino
Keyword(s):  
Dietary Restriction ◽  
General Health ◽  
Alternative Fuels ◽  
Ketone Bodies ◽  
Medium Chain Triglycerides ◽  
Clinical Applicability ◽  
Improve Compliance ◽  
Therapeutic State ◽  
And Performance ◽  
Glucose Availability

Nutritional ketosis produces a nonpathological hyperketonemia resulting from decreased glucose availability, lower insulin, and increased fat oxidation. However, the restrictive nature of the ketogenic diet (KD) has limited the clinical applicability of therapeutic ketosis, due to practical considerations. Emerging data suggests that many of the benefits of the KD are mechanistically attributable to the ketone bodies or specific medium chain triglycerides, and this has motivated investigators to develop strategies to further augment the efficacy of the KD or use metabolic-based supplements to circumvent the need for dietary restriction to improve compliance and the maintenance of this therapeutic state. This section, “Ketone-Based Metabolism: General Health and Metabolic Alternatives,” includes chapters that discuss the expanding medical and performance applications of nutritional ketosis and the emerging science of ketones and other related metabolites as alternative fuels and potent signaling molecules.

Use of R-beta-[1-11C]hydroxybutyrate in PET studies of regional cerebral uptake of ketone bodies in humans

1995 ◽  
Vol 269 (5) ◽  
pp. E948-E959 ◽  
Author(s):  
G. Blomqvist ◽  
J. O. Thorell ◽  
M. Ingvar ◽  
V. Grill ◽  
L. Widen ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Animal Studies ◽  
Time Course ◽  
Ketone Bodies ◽  
Tracer Uptake ◽  
Utilization Rate ◽  
Rate Limiting Step ◽  
Positron Emission ◽  
Beta Hydroxybutyrate ◽  
The Brain

A method for determining regional cerebral utilization of ketone bodies in humans is described. After a bolus injection of R-beta-[1-11C]hydroxybutyrate, the time course of the tracer in the brain was measured with positron emission tomography in five healthy volunteers. The regional cerebral blood flow was measured separately. The tracer uptake in the brain could be well described by a single rate constant, indicating that the concentration of unmetabolized ketone bodies in the brain is very low and that transport across the blood-brain barrier is the rate-limiting step. At an average plasma concentration of beta-hydroxybutyrate of 0.043 mumol/ml, the utilization rate was estimated to be 0.48 nmol.ml-1.min-1. In accordance with previous animal studies, the utilization rate was found to increase almost linearly with increasing plasma concentration of beta-hydroxybutyrate. Furthermore, the utilization was higher in gray than in white matter. Finally, the ratio between the utilization in the basal ganglia and the brain as a whole was lower for ketone bodies than for glucose.

scholarly journals Immunometabolic Stress and Ketone Bodies in Disorders of the Aging Brain

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 348-348
Author(s):  
John Newman
Keyword(s):  
Older Adults ◽  
Acute Inflammation ◽  
Ketone Bodies ◽  
Innate Immune ◽  
Energy Utilization ◽  
Aging Brain ◽  
Geriatric Syndrome ◽  
Risk Of Death ◽  
Increased Risk ◽  
The Brain

Abstract Delirium is an acute confusional state that is a common complication of acute illness in older adults, and is associated with increased risk of death, disability, and dementia. Delirium in older adults is an example of a geriatric syndrome, with multifactorial, multi-system causes that include existing aging-related physiological changes as well as external acute stressors. Its pathophysiology delirium is not well understood but may include glycolytic energy deficits associated with acute inflammation in the brain. The endogenous ketogenic system provides ketone bodies as a lipid-derived alternative to glucose for cellular energy, and ketone bodies are increasingly understood to have immunomodulatory effects particularly on innate immune cells. We used a mouse model of acute inflammation-associated behavioral change to investigate how age-related differences in energy utilization in the brain affect delirium-like phenotypes, focusing on energy metabolism and innate immune activation in the brain as an example of immunometabolic approaches to geriatric syndromes.

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