This episode will make a great companion for a long drive.
An essential checklist for cognitive longevity — filled with specific exercise, heat stress, and omega-3 protocols for boosting BDNF. Enter your email, and we'll deliver it straight to your inbox.
Stress, pathology, and aging can alter brain energy metabolism. During times of impaired brain energy, the brain may prefer to use ketones as a fuel source. The use of alternate fuel sources allows glucose to be spared for the metabolic pathways that require it. In this clip, Dr. Dominic D'Agostino discusses the metabolic flexibility of the brain to use various substrates, including ketones, for energy.
Rhonda: I think there's a lot of parallels between ketone bodies and ketone supplements and how they're not only being used as a preferential source of energy in the brain. Do you know anything about this, about, like, how frees up glucose then to be used for other...
Dom: Glucose sparing.
Rhonda: ...metabolic pathways? Yeah, glucose sparing.
Dom: Yeah, it's thought that some of the work by Stephen Cunnane, I think, is shedding light on this, too.
Rhonda: Where is he at?
Dom: He's in Canada. I forget the institute that he's at. Joe LaManna has done some similar work and he's at Case Western and looked at the, kind of, the interaction of what does the brain prefer...what's the preferred fuel source for the brain. I get this question a lot. I think it depends on, you know...I don't know if it's right to say that the brain always prefers ketones.
Rhonda: The brain cell we're talking about, for one. The neuron, astrocytes.
Dom: Neurons and astrocytes. But, yeah, I guess, I mean, maybe we're definitely biased towards understanding neurons relative to astrocytes.
Rhonda: I think most people that ask me that question are....
Dom: Astrocytes are fascinating. I think we need to study that more. But I think in the context of, like, aging and a context of traumatic brain injury or pathology, I think the brain will really prefer to use ketones because...or in the context of some kind of stress hypoglycemia or something like that, I think the brain will also prefer to use ketones.
Rhonda: Yeah, so why do you think that is?
Dom: Well, I think...
Rhonda: I might have my own reasons why.
Dom: There's a whole host of reasons or things that can cause impaired brain energy, brain glucose metabolism and that could be internalization of the GLUT3 transporter, which occurs...it's kind of linked to Alzheimer's pathology.
Rhonda: GLUT...
Dom: GLUT3, yeah. And there's a couple of key enzymes that are either deficient or not active like they should be, pyruvate dehydrogenase complex is deficient.
Rhonda: So wait, are these in...are the GLUT3 changes in astrocytes or in neurons?
Dom: Primarily in neurons.
Rhonda: Neurons, okay.
Dom: So the glucose transporter in neurons.
Rhonda: So if neurons are using lactate primarily...the astrocytes are actually what's...
Dom: Shuttling a lot.
Rhonda: The astrocytes are using glucose and that's why the brain needs glucose and they're producing the lactate. The neurons are using the lactate because it's getting shunted and converted into pyruvate.
Dom: And the contribution of that is not completely known, but it's pretty significant contribution during hypoxia, I would think.
Rhonda: There's been studies out there showing that not just during hypoxia, but actually just under normal physiology that...
Dom: It's a key player.
Rhonda: It is, yeah, the neurons are getting lactate continually from astrocytes which are generating it, but that the astrocytes become aberrant during...for whatever reason, it's not known, Alzheimer's leaves traumatic brain injury, so they can't make that lactate and neurons have to start using the glucose, which then is, but I mean, that's just one.
Dom: Yeah, I've heard about that, I haven't looked into that. Yeah, so there's some key enzymes then that people look at not only just the lactate levels...
Rhonda: I think that...I have no idea what they're looking at, but for the pyruvate dehydrogenase complex, you're saying that's also aberrant in some of these disease states because then, you wouldn't be able to use the lactate because you couldn't convert it into pyruvate. So anyways, it's all kind of, I totally interrupted you, though, but you were talking about... What were you talking about, the aberrant enzymes, like GLUT3 and pyruvate dehydrogenase, and how these are aberrant in different neurological disorders.
Dom: Yeah. So I think, I think, well, maybe the question we're trying to get at is the contribution of ketones as a brain energy source and especially in, sort of, in academia and circles where I teach, it's not even, still not really known, it's not really accepted or understood that much. But I think the capacity, the metabolic flexibility of the brain to be able to use ketones, we can exploit that and we do that with nutritional ketosis, and it's altering brain energy metabolism and the neuropharmacology of the brain in ways we don't completely understand now, meaning the neurotransmitters in the brain. So I could draw off GABA. So you have more GABA, the GABA-to-glutamate ratio is shifted in favor of higher GABA. So there's a higher GABA-to-glutamate ratio when one is on the ketogenic diet.
Rhonda: In people that are not having...in normal people, as well? Just, like, in general?
Dom: Yeah.
Rhonda: Interesting.
Dom: It's thought that, and there's different reasons for that. There's glutamic acid decarboxylase is an enzyme.
Rhonda: Is that how it helps with epilepsy?
Dom: That's part of it. I think there's about 20 or more things going on if you look at all the signaling pathways [crosstalk 00:39:37] actually what happens, yeah, with metabolism, but I think a key player in that is an elevation of GABA to glutamate. And we need glutamate to make GABA, right, but the enzyme is elevated and the pathways are shift in favor of more glutamate to GABA, which has a stabilizing effect on your cell membrane and neural interactivity, in general.
Rhonda: How readily do ketones cross the blood-brain barrier?
Dom: It's thought up to five millimolar, maybe six, seven millimolar, they can readily cross the blood-brain barrier.
Rhonda: You have to get that high before they start crossing?
Dom: No they start impeding once you get levels up that high. It hasn't really been studied in-depth. We did brain metabolomics to show that when we looked at the ketone levels in brain tissue and ketone levels in the blood, and there's a high correlation there. Interestingly, we had a diet, too, that was high in medium-chain fatty acids. And although I heard the medium-chain fatty acids could readily cross the blood-brain barrier long-chain fatty acids typically don't, short-chain fatty acids sort of do. But we found very high levels of medium-chain fatty acids indicative of them and these were normal, healthy animals. So when you take medium-chain fatty acids, they are readily from the looks of our metabolomic data, just readily crossing the blood-brain barrier and capable of being used as fuel...
Rhonda: That's fascinating, I had no idea.
Dom: ...which is very, yeah, it's really interesting. I heard about that, but when you see the data it's at really high levels.
Rhonda: So when they're in the brain, then how are they...so then what happens? So they're used...
Dom: Yeah, their medium-chain fatty acids can be oxidized just like fatty acids for fuel, yeah...
Rhonda: Wow, interesting.
A neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, cognitive dysfunction, and behavioral changes. The pathological hallmarks of Alzheimer's disease include amyloid-beta plaques, tau tangles, and reduced brain glucose uptake. Most cases of Alzheimer's disease do not run in families and are described as "sporadic." The primary risk factor for sporadic Alzheimer's disease is aging, with prevalence roughly doubling every five years after age 65. Roughly one-third of people aged 85 and older have Alzheimer's. The major genetic risk factor for Alzheimer's is a variant in the apolipoprotein E (APOE) gene called APOE4.
Star-shaped cells found in the brain and spinal cord. Astrocytes facilitate neurotransmission, provide nutrients to neurons, maintain neuronal ion balance, and support the blood-brain barrier. Astrocytes also play a role in the repair and scarring process of the brain and spinal cord following traumatic injuries.
A highly selective semi-permeable barrier in the brain made up of endothelial cells connected by tight junctions. The blood-brain barrier separates the circulating blood from the brain's extracellular fluid in the central nervous system. Whereas water, lipid-soluble molecules, and some gases can pass through the blood-brain barrier via passive diffusion, molecules such as glucose and amino acids that are crucial to neural function enter via selective transport. The barrier prevents the entry of lipophilic substances that may be neurotoxic via an active transport mechanism.
Any of a group of complex proteins or conjugated proteins that are produced by living cells and act as catalyst in specific biochemical reactions.
A molecule composed of carboxylic acid with a long hydrocarbon chain that is either saturated or unsaturated. Fatty acids are important components of cell membranes and are key sources of fuel because they yield large quantities of ATP when metabolized. Most cells can use either glucose or fatty acids for this purpose.
A neurotransmitter produced in the brain that blocks impulses between nerve cells. GABA is the major inhibitory neurotransmitter in gray matter.
A survival mechanism the brain relies on during starvation. Glucose sparing occurs when the body utilizes fatty acids as its primary fuel and produces ketone bodies. The ketone bodies cross the blood-brain barrier and are used instead of glucose, thereby “sparing” glucose for use in other metabolic pathways, such as the pentose-phosphate pathway, which produces NADPH. NADPH is essential for the production of glutathione, one of the major antioxidants used in the body and brain.
Facilitates the transport of glucose across the cell membrane of skeletal muscles and adipose tissue cells, thereby removing glucose from the bloodstream.
An amino acid found in high concentration in every part of the body. In the nervous system, glutamate is by a wide margin the most abundant neurotransmitter in humans. It is used by every major excitatory information-transmitting pathway in the vertebrate brain, accounting in total for well over 90% of the synaptic connections in the human brain.
An enzyme that catalyzes the decarboxylation of glutamate into GABA, using vitamin B6 as a cofactor.
Abnormally low blood glucose. Hypoglycemia can occur due to low glycogen stores, diabetes medications, or other drugs. Maternal alcohol consumption can cause hypoglycemia in breastfed infants. Symptoms of hypoglycemia include confusion, heart palpitations, shakiness, and anxiety.
Condition in which the body or a region of the body is deprived of adequate oxygen supply. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body.
A diet that causes the body to oxidize fat to produce ketones for energy. A ketogenic diet is low in carbohydrates and high in proteins and fats. For many years, the ketogenic diet has been used in the clinical setting to reduce seizures in children. It is currently being investigated for the treatment of traumatic brain injury, Alzheimer's disease, weight loss, and cancer.
Molecules (often simply called “ketones”) produced by the liver during the breakdown of fatty acids. Ketone production occurs during periods of low food intake (fasting), carbohydrate restrictive diets, starvation, or prolonged intense exercise. There are three types of ketone bodies: acetoacetate, beta-hydroxybutyrate, and acetone. Ketone bodies are readily used as energy by a diverse array of cell types, including neurons.
Lactate is thought to participate in a sort of "lactate shuttle" where, after being produced in muscle from exercise, it is transported in to tissues like the heart, and brain, where it is used as an energy source. Lactate is one of many molecules that falls under a loose group of molecules referred to as exerkines, a broad group of exercise-induced hormonal-like factors. Evidence suggests that lactate is the preferred fuel of the brain. Additionally, rodent studies suggest that lactate mediates some of the benefits of exercise on learning and memory via inducing neuronal brain-derived neurotrophic factor (BDNF) expression.[1] In clinical studies, lactate shows promise as a treatment for inflammatory conditions including traumatic brain injury and as a means to deliver fuel to working muscles.
A class of saturated fats. Medium-chain triglycerides are composed of medium-length fatty acid chains (six to 12 carbons long) bound by a glycerol backbone. They occur naturally in coconut oil, palm oil, and butter, but they can also be synthesized in a laboratory or food processing setting. Evidence suggests that MCT therapy improves cognitive function in older adults with Alzheimer's disease.[1] Examples of MCTs include caprylic acid (C8), capric acid (C10), and lauric acid (C12).
The thousands of biochemical processes that run all of the various cellular processes that produce energy. Since energy generation is so fundamental to all other processes, in some cases the word metabolism may refer more broadly to the sum of all chemical reactions in the cell.
One of the enzymes involved in the process of converting pyruvate, which is derived from glucose, into energy in the form of ATP inside of the mitochondria.
Damage to the brain caused by a sudden blow, penetrating injury, or lack of oxygen, ranging from mild to severe. TBIs can induce a wide range of short- or long-term changes in the brain that affect thinking, sensation, language, personality, and emotion. In addition, TBI may increase the risk for developing epilepsy, Alzheimer’s disease, Parkinson’s disease, and other brain disorders. Nearly 75 percent of TBIs that occur each year are concussions or other forms of mild TBI. Even mild TBIs damage the delicate tissues and blood vessels of the brain and can result in altered brain function that can persist for days, weeks, or months. Approximately 15 percent of concussed athletes experience symptoms as long as one year after their injury, a condition called persistent post-concussion syndrome, or PPCS, typically after returning to play too quickly.
Learn more about the advantages of a premium membership by clicking below.
The FoundMyFitness Q&A happens monthly for premium members. Attend live or listen in our exclusive member-only podcast The Aliquot.