Ketones were first discovered in the urine of diabetic patients in the mid-19th century. For nearly 50 years they were mistakenly considered abnormal and unwanted byproducts of faulty fat oxidation (1).
The ketogenic diet’s modern origins in the U.S. date back to the 1920s, when physicians first started administering it for epileptic seizures.
Ketones: What We Know Today
Ketone bodies ─ acetoacetate, beta hydroxybutyrate (BHB) and acetoacetate ─ are utilized as an energy source by the body in the absence of carbohydrates when a depletion of glycogen occurs (2). Liver mitochondria produce ketones from fatty acids during periods of fasting and starvation.
A growing body of established research points to a role for exogenous ketone administration in seizure disorders and rare genetic conditions.
Some emerging research suggests specific benefits for BHB, alone or in combination with medium-chain triglycerides (MCTs), for conditions such as Angelman syndrome, epilepsy, and multiple acyl-CoA dehydrogenation deficiency (MADD).
Research into BHB ─ much of it experimental ─ has so far been broadly aggregating around inflammation, metabolism, neuroprotection, and epilepsy.
BHB and Inflammation
BHB levels are elevated by starvation, caloric restriction, a ketogenic diet and high-intensity exercise (3). A recent eight-week study looked at the effects of a ketogenic diet and exercise capacity in mice (4).
The researchers found that a ketogenic diet appeared to beneficially re-model lipid metabolism and prevent muscle damage by modulating the secretion of inflammatory cytokines, such as interleukin-6 (IL-6).
In addition to reprogramming lipid metabolism, experimental research has shown that BHB plus MCT during nutritional ketosis may “reprogram energy metabolism and decrease the proliferation of cancer cells (5).”
Other recent research by Kong et al. (6) specifically studied BHB in experimental and in vitro models of inflammation and neuroprotection.
In an in vitro arm of this study, BHB was found to be anti-oxidative. Inhibiting the production of reactive oxygen species (ROS) via suppression of class I histone deacetylases (HDACs), BHB decreased levels of free-radical-producing nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and increased expression of FOX03a (forkhead box class O 3a) transcription factors that, in turn, upregulate antioxidants such as manganese-dependent superoxide dismutase (MnSOD).
The role of inflammasomes. Inflammasomes are multi-protein signaling complexes that trigger activation of inflammatory cysteine-aspartic proteases (caspases) and the maturation of interleukin-1β.
Among inflammasome complexes, the NLRP3 (NLR family pyrin domain containing 3) inflammasome has been linked to various human auto-inflammatory and auto-immune diseases.
In 2015, researchers from Yale University noted that BHB reduced or blocked several markers of NLRP3-mediated inflammation in an ex vivo model including interleukin (IL)-1β and IL-18 (3).
In fact, the Yale researchers postulated that the anti-inflammatory effects of both caloric restriction and ketogenic diets may be linked to BHB-mediated inhibition of the NLRP3 inflammasome (3).
Recently, investigators from Japan’s Tottori University have also begun to explore the potential for BHB in mediating inflammation-linked markers of depression (7).
It is believed that the stress-induced release of IL-1β and tumor necrosis factor (TNF)-α is tightly regulated by the NLRP3 inflammasome (8).
The Tottori University researchers found, in a rodent model of depression, that repeated administration of BHB attenuated behaviors related to chronic unpredictable stress (CUS)-caused depression and anxiety.
Other researchers have linked metabolic changes after stress to higher levels of Histone3-lysine9-β-hydroxybutyrate (H3k9bhb) (9). They found that exogenous administration of BHB ameliorated depressive behaviors.
Reduced inflammation and neuroprotection. Linking BHB to decreased inflammation, pain reduction and neuronal recovery, researchers gave BHB to mice with induced spinal cord injuries (10).
D-β-hydroxybutyrate (D-BHB) partly prevented loss of motor neurons, reduced inflammation and oxidative stress, and improved mitochondrial function in injured mice.
BHB’s anti-inflammatory effects stemmed from its suppression of NLRP3 inflammasome activation and its effects on reduced over-expression of both IL-1β and IL-18.
BHB and Neuroprotection
It is known that administration of exogenous ketones is neuroprotective in such neurological disorders as epilepsy (11).
Researchers in Denmark set out to uncover the underlying mechanisms for administration of exogenous ketones and whether these effects are brain region-specific or not (12).
In a randomized, controlled trial of healthy human subjects, infusions of 3-hydroxybutyrate yielded reduced reliance on cerebral glucose, maintained oxygen utilization, and increased cerebral blood flow by 30% in all measured regions of the brain.
The authors posit that these effects directly contribute to the “neuroprotective effects of ketone bodies.”
In a recent animal study, researchers tested the potential of D-BHB to substitute for glucose as an energy substrate during glucose depletion and to prevent the subsequent death of neurons (13).
In a series of experiments that utilized male Wistar rats and ex vivo cell cultures, the authors found that D-BHB reduces production of ROS in distinct cortical areas and hippocampal sub-regions efficiently preventing neuronal death in the cortex of hyperglycemic rats.
Alzheimer’s disease. It is well established that deposition of β-amyloid peptide in senile plaques and cerebral vasculature is a hallmark change associated with Alzheimer’s disease (AD) (14).
The underlying neurotoxic mechanisms of this phenomenon are linked to oxidative-stress-induced apoptosis, which leads to widespread loss of neurons.
In another recent animal study, researchers demonstrated the neuroprotective effects of D-BHB injected directly into the hippocampus of rats. Overall, BHB administration effectively prevented neuronal apoptosis and deposition of beta-amyloid peptide (15).
In a study carried out by the Barrow Neurological Institute in Phoenix, researchers aimed to assess whether exogenous ketones, including BHB, can serve a larger role than that of mitochondrial energy substrates in reference to AD (16).
In this mouse study, the authors discovered a novel neuroprotective mechanism of ketones which blocked the entry of the toxic beta-amyloid peptide precursor and amyloid-42 into neurons. This rescued the activity of mitochondrial complex I ─ which is significant since it oxidizes NADH and reduces ubiquinone to ubiquinol ─ reduced oxidative stress and improved synaptic plasticity.
These researchers also showed that peripheral administration of ketones significantly reduced levels of beta-amyloid plaque, greatly improving learning and memory ability in a mouse model of AD. The authors speculated that ketones, including BHB, could be used in preventive approaches to the disease.
Epilepsy. While beneficial roles for a ketogenic diet, in general, and BHB in particular, have been shown in reference to metabolic diseases with features that include epilepsy, researchers in Sweden decided to look at short-term and long-term effects of a ketogenic diet on disease course and outcomes in pediatric patients with pyruvate dehydrogenase complex deficiency (17).
Pediatric patients with a median age of six years at the time of study registration were treated with a ketogenic diet for an average 2.9 years.
The ketogenic diet yielded positive effects in markers of epilepsy, ataxia, sleep disturbances, speech/language development, social functioning; and frequency of hospitalizations.
In an earlier study out of South Korea, scientists investigated the use of BHB in a rat model of infantile spasms (IS) (18). The results showed that prolonged treatment with BHB resulted in a significant delay in the onset and frequency of spasms.
trumacro™ Nutrition is committed to improving lives through the therapeutic use of ketogenic (low-carb, high-fat) products and technologies. Its ambitious program of scientific discovery specific to exogenous ketones is supported by research and a robust patent portfolio.
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- Qian J, et al. D-β-hydroxybutyrate promotes functional recovery and relieves pain hypersensitivity in mice with spinal cord injury.” Br J Pharmacol. 2017;174(13):1961-1971.
- Ciarlone SL, et al. “Ketone ester supplementation attenuates seizure activity, and improves behavior and hippocampal synaptic plasticity in an Angelman syndrome mouse model.” Neurobiol Dis. 2016;96:38-46.
- Svart M, et al. “Regional cerebral effects of ketone body infusion with 3-hydroxybutyrate in humans: Reduced glucose uptake, unchanged oxygen consumption and increased blood flow by positron emission tomography. A randomized, controlled trial.” PLoS One. 2018;13(2):e0190556
- Julio-Amilpas, et al. “Protection of hypoglycemia-induced neuronal death by β-hydroxybutyrate involves the preservation of energy levels and decreased production of reactive oxygen species.” J Cereb Blood Flow Metab. 2015 May;35(5):851-860.
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