HoldsUp

FoundMyFitness · 2014-12-02 · Rhonda Patrick (host), George Brooks

George Brooks, Ph.D. on Lactate Shuttle Theory, Relevance for Traumatic Brain Injury & More

42 claims checked against research: 1 contradicted 1 overstated 1 needing context 37 supported 2 unverified

37

Supported by research

0:00:30Rhonda Patrick (host)supportedmoderate

Lactate produced during exercise is used by the heart and brain as a preferred source of energy.

"and that is that it is something that is produced during exercise and it's used by, you know, the heart and the brain as a preferred source of energy." (said at 0:00:30)

Extensive physiological and tracer studies support that lactate produced during exercise serves as a major and preferred oxidative fuel source for both the myocardium (heart) and the brain. Through the cell-cell lactate shuttle, circulating lactate taken up by cardiac myocytes and cerebral neurons/astrocytes is readily oxidized for ATP production, sparing or displacing other substrates such as glucose during periods of elevated blood lactate.

0:03:05George Brookssupportedhigh

Glycolysis and lactate production occur continuously in all cells, where lactate acts as a fuel, a precursor for blood glucose, and a signaling molecule.

"glycolysis—the breakdown of sugar and glycogen—happens all the time in all cells, and we use it. We use it as a fuel. We use it to support our blood sugar level. We use it as a signaling molecule to activate certain metabolic processes. It's made in some cells, and it's used in other cells." (said at 0:03:05)

Extensive metabolic physiology research confirms the speaker's statement. Rather than being merely an anaerobic waste product, lactate is continuously produced under fully aerobic conditions and shuttles between producer (source) and consumer (sink) cells. Across human and mammalian studies, lactate is established as fulfilling three major metabolic roles: serving as a major oxidative fuel for tissues such as the heart, brain, and skeletal muscle; acting as the primary gluconeogenic precursor in the liver and kidneys to maintain blood glucose levels; and functioning as an autocrine, paracrine, and endocrine signaling molecule.

0:06:37George Brookssupportedmoderate

Lactate transporters are located in plasma membranes and within the mitochondrial reticulum as lactate/pyruvate transporters.

"our unique contribution was to find that not only are they in the plasma membranes of muscles and heart and other tissues, but they're also in the mitochondria. They are the lactate/pyruvate transporter." (said at 0:06:37)

Published cell biology and biochemical studies confirm that monocarboxylate/lactate transporters (such as MCT1) are located both in plasma/sarcolemmal membranes and within the mitochondrial reticulum/inner mitochondrial membrane of cardiac muscle, skeletal muscle, and other tissues, where they transport monocarboxylates like lactate and pyruvate into mitochondria for oxidation.

0:08:09George Brookssupportedmoderate

Endurance training leads to lower blood lactate at any given power output because trained individuals have superior lactate clearance and utilization.

"So one of the things we found is that the classic training response that people have is to have a lower lactate at any power output. So if I would compare myself to a young, healthy athlete, that athlete would actually be producing more lactate than I would be, but my lactate level would be really high because I'm limited in my ability to take it up and use it, whereas the athlete is superior in terms of clearing lactate and using it as a fuel and using it as a gluconeogenic precursor." (said at 0:08:09)

Human and animal metabolic tracer studies confirm that endurance training results in lower arterial blood lactate concentrations at given absolute and relative power outputs. This adaptation is largely driven by enhanced metabolic clearance rate (uptake, oxidation as fuel, and gluconeogenic precursor utilization) in active skeletal muscle and other tissues, in addition to reduced net lactate release at submaximal workloads.

0:08:41George Brookssupportedmoderate

Trained athletes produce more lactate than untrained individuals, but clear and remove it more rapidly.

"And athletes actually produce more than people who are less capable or less highly trained, but they remove it; they use it." (said at 0:08:41)

Tracer kinetic studies in humans demonstrate that trained endurance athletes have higher capacities for both lactate production (rate of appearance) and lactate clearance/oxidation (rate of disposal and metabolic clearance rate) compared to untrained individuals. While lactate production is lower in trained individuals at the same absolute submaximal workload due to enhanced mitochondrial oxidative efficiency, at maximal workloads and at the lactate threshold, athletes achieve higher absolute rates of lactate production and simultaneously clear and utilize lactate much more rapidly.

0:09:13George Brookssupportedmoderate

Physical exercise training can double the amount of mitochondrial mass in human muscle.

"So you can actually double the amount of mitochondria you have in your muscle by training. That's really one of the most incredible adaptations we know about." (said at 0:09:13)

Substantial evidence in exercise physiology demonstrates the remarkable plasticity of skeletal muscle mitochondrial content in response to exercise training. While typical short- to moderate-term training interventions in previously untrained adults commonly produce a 30% to 50% increase in mitochondrial content and volume density, prolonged or high-volume endurance training can result in up to a two-fold (100%) difference compared to sedentary baseline levels, as observed in longitudinal training adaptations and cross-sectional comparisons between trained athletes and sedentary controls.

0:09:13George Brookssupportedmoderate

Exercise training can double the quantity of lactate transporters in skeletal muscle.

"And as well, you can double the amount of lactate transporters." (said at 0:09:13)

Endurance and high-intensity interval training significantly upregulate the expression and protein content of monocarboxylate transporters (primarily MCT1 and MCT4) in skeletal muscle. Clinical training studies have demonstrated increases of up to ~90% (near doubling) in total muscle MCT1 content after endurance training programs, alongside increases in mitochondrial and sarcolemmal transporter abundance.

0:11:46George Brookssupportedvery low

Incubating muscle cells with lactate upregulates over 600 genes associated with muscle adaptation and mitochondrial biogenesis.

"But we know from our studies that we've done with incubated muscle cells that if we just take muscle cells and we incubate them with lactate, we'll upregulate over 600 genes, all the genes basically of muscle adaptation." (said at 0:11:46)

In vitro experimental work demonstrates that incubating muscle cells with lactate stimulates cell signaling cascades and activates a broad transcriptional network, inducing the expression of monocarboxylate transporters (such as MCT1), mitochondrial components, and genes regulating mitochondrial biogenesis and metabolic adaptation. Because this evidence is derived entirely from isolated cell culture models rather than in vivo human physiological trials, the overall certainty is graded as very low.

0:16:50George Brookssupportedmoderate

Glycolysis produces lactate rather than lactic acid, and exercise acidosis is caused by protons liberated from ATP hydrolysis.

"Well, if you look at the glycolytic pathway, it actually makes lactate. But lactate is a pretty strong acid, so it associates with water, and a certain amount of acidosis that will be associated with the lactate itself. But glycolysis actually makes lactate, not lactic acid. The acidosis, the hydrogen ions, come from other processes like the splitting of ATP, which is our high-energy source. When we split that, we liberate a proton." (said at 0:16:50)

The speaker's main biochemical assertion—that glycolysis produces lactate rather than lactic acid and that exercise-induced acidosis is driven by protons released from non-mitochondrial ATP hydrolysis—is supported by published biochemical analyses of metabolic pathways during high-intensity exercise. In cellular conditions, the lactate dehydrogenase reaction converts pyruvate to lactate while consuming protons (acting as a metabolic buffer rather than an acid producer). Proton accumulation during intense muscle work primarily originates from the hydrolysis of ATP to ADP and inorganic phosphate when ATP regeneration demands exceed mitochondrial oxidative phosphorylation capacity.

0:17:51George Brookssupportedhigh

Lactic acid has a pKa of approximately 3, meaning it is completely dissociated into lactate anion and a proton at physiological pH.

"Well, the pKa is really is about 3. So if there was lactic acid, it would be completely dissociated to its lactate anion and a proton." (said at 0:17:51)

Lactic acid is a weak organic acid with an acid dissociation constant (pKa) of approximately 3.86. Because physiological pH (typically ~7.0 to 7.4 in human tissues and blood) is more than three pH units above this pKa, lactic acid is almost entirely dissociated (>99.9%) into its conjugate base, the lactate anion, and a proton (H+).

0:18:21George Brookssupportedlow

Ingesting polyLactate during exercise slightly elevates blood pH by binding endogenous protons.

"And so when we take our polyLactate and people consume it while they're exercising, their blood pH actually rises slightly. So you can use the salt of an acid as a base, and so the endogenous acid combined with the lactate we give is removed as lactic acid, and so it actually alkalizes the blood." (said at 0:18:21)

A double-blind, crossover trial in trained cyclists found that ingesting a polylactate formulation (containing polylactate and sodium lactate) before and during prolonged cycling resulted in significantly higher blood pH and bicarbonate levels compared to a glucose polymer drink or placebo control. Ingesting lactate salts provides a conjugate base that can bind hydrogen ions or consume protons during metabolic clearance, thereby providing a mild blood-alkalizing and buffering effect during exercise. The certainty is graded low due to very small sample sizes in the available trials.

0:20:26George Brookssupportedmoderate

Doubly labeled water database records show that lean, healthy, free-living individuals engage in approximately one hour of daily physical activity.

"And what we found by looking at the doubly labeled water database, which was generously donated by almost every investigator whoever did a study, that people who are healthy and lean and freely living—that is eating whatever they want—they're active about an hour a day." (said at 0:20:26)

The speaker's statement accurately reflects findings derived from pooled doubly labeled water (DLW) databases. The DLW method measures total energy expenditure in free-living humans, and large pooled databases compiled from contributing global investigators (such as those analyzed for dietary reference intake equations and the IAEA DLW database consortium) demonstrate that weight-stable, healthy, normal-weight adults typically have physical activity levels (PAL) corresponding to approximately 60 minutes of moderate physical activity daily.

0:20:58George Brookssupportedhigh

Thirty minutes of daily exercise improves cardiovascular function and lowers risk for heart disease, diabetes, and certain cancers, but is insufficient to manage body weight.

"Now, it's true there's good epidemiological research to indicate that if you do some activity, like 30 minutes a day, you'll improve cardiovascular function, you'll reduce your risk of heart disease and diabetes and maybe some forms of cancer, but that's not enough activity to control your body weight." (said at 0:20:58)

Substantial epidemiological and randomized trial evidence supports the speaker's claim. Public health guidelines recommending approximately 30 minutes per day of moderate-intensity physical activity (150 minutes per week) are well-established to improve cardiorespiratory fitness and significantly lower the incidence of cardiovascular disease, type 2 diabetes, and various cancers (such as colon and breast cancer). However, consensus guidelines, including the American College of Sports Medicine (ACSM) position stands, demonstrate that 150 minutes per week of physical activity without dietary restriction results in only modest weight loss. For clinically meaningful weight loss, long-term body weight maintenance, or prevention of weight regain, substantially higher volumes of physical activity (typically >250 to 300 minutes per week, or roughly 45–60 minutes per day) are generally required.

0:23:32Rhonda Patrick (host)supportedvery low

Lactate directly stimulates the production of brain-derived neurotrophic factor (BDNF).

"In terms of BDNF, which is a neurotrophic factor, it actually stimulates the growth of new brain cells. Lactate specifically has been shown to stimulate BDNF, which is quite interesting, because..." (said at 0:23:32)

Preclinical studies demonstrate that lactate, produced peripherally during exercise or administered directly, crosses the blood-brain barrier and stimulates hippocampal brain-derived neurotrophic factor (BDNF) expression. In rodent models, this induction occurs via a pathway involving SIRT1 activation, PGC-1α, and FNDC5/irisin signaling, as well as the regulation of mitochondrial quality control systems. Because the direct causal mechanism has been established in animal and in vitro models, the certainty is rated very low.

0:24:35Rhonda Patrick (host)supportedvery low

Lactate stimulates locus coeruleus neurons in the brain to release norepinephrine.

"very recently, I think it was a group in the Netherlands, they showed that lactate actually stimulates these neurons in a brain region called the locus coeruleus, which is where all the norepinephrine neurons are. So these neurons that make norepinephrine—norepinephrine is that neurotransmitter that's involved in focus and attention—and they've shown that actually specifically lactate stimulates the release of norepinephrine from those locus coeruleus neurons." (said at 0:24:35)

Preclinical experimental research confirms that lactate acts as a signaling molecule in the brain's locus coeruleus (LC) to excite noradrenergic neurons and trigger norepinephrine release. In rodent models, both astrocytic release of L-lactate and exogenous application of physiological concentrations of L-lactate depolarized LC neurons and stimulated the release of norepinephrine via a receptor-mediated, cAMP-dependent mechanism independent of its metabolic use. Because the available evidence consists of animal and cellular mechanistic studies, the certainty is graded as very low.

0:25:06George Brookssupportedhigh

Lactate transporters are highly expressed throughout capillary endothelial cells, astrocytes, and neurons in the brain.

"Things get into the brain cells by transporters, and these lactate transporters are highly expressed in all the capillaries in our body, including in our astrocytes and our neurons." (said at 0:25:06)

Monocarboxylate transporters (MCTs), which mediate the transport of lactate, pyruvate, and ketone bodies, are widely expressed across the blood-brain barrier and central nervous system parenchyma. Specific isoforms carry out transport in distinct cell types: MCT1 is expressed on microvascular capillary endothelial cells and astrocytes; MCT4 is predominantly expressed by astrocytes; and MCT2 is the principal lactate transporter expressed by neurons.

0:22:32George Brookssupportedmoderate

Regular physical activity reduces the incidence of colon cancer and breast cancer.

"So for instance, if somebody is regularly active, why is the incidence of colon cancer reduced? Why is the incidence of breast cancer reduced?" (said at 0:22:32)

Large-scale prospective cohort studies, systematic reviews, and meta-analyses consistently demonstrate that regular physical activity is associated with a statistically significant reduction in the incidence of both colon cancer and breast cancer. In an umbrella review evaluating 22 cancer sites, colon and breast cancers had the strongest epidemiological evidence for protective associations with physical activity. A dose-response meta-analysis of prospective cohorts found that high physical activity levels were associated with a 21% reduction in colon cancer risk (relative risk 0.789) and a 14% reduction in breast cancer risk (relative risk 0.863) compared with insufficient physical activity.

0:26:37Rhonda Patrick (host)supportedlow

In patients with moderate to severe traumatic brain injury, elevated blood lactate levels correlate with better clinical and cognitive recovery if the blood-brain barrier is intact.

"I read a couple of papers recently on this topic of lactate in terms of patients that had moderate to severe traumatic brain injury, and they had higher levels of lactate in their bloodstream, they had a better outcome. And those patients that did not have an intact blood-brain barrier, that wasn't the same for them." (said at 0:26:37)

The claim that acute lactate metabolism and systemic availability correlate with better cognitive recovery following traumatic brain injury (TBI) is supported by clinical metabolic studies (such as research from the UCLA TBI group led by Glenn et al.). In moderate-to-severe TBI, cerebral lactate uptake and peripheral lactate mobilization serve as alternative fuels during acute post-injury glucose metabolic crises, and cerebral metabolic rate of lactate significantly predicted long-term recovery of frontal-temporal cognitive function (accounting for 22% of variance). However, the specific caveat regarding blood-brain barrier (BBB) integrity is contextually nuanced: lactate normally crosses the intact BBB via monocarboxylate transporters (MCTs) to fuel neurons and astrocytes, and severe disruption of the BBB accompanied by severe tissue ischemia can lead to pathological local lactate accumulation, which differs in clinical meaning from systemic/arterial substrate utilization.

0:18:51George Brookssupportedmoderate

Administering lactate salts can mitigate cerebral swelling and acidosis following traumatic brain injury.

"And by giving salts of lactate, we can mitigate the swelling, we can provide fuel, and we can manage the acidosis which occurs." (said at 0:18:51)

Clinical studies and randomized controlled trials in patients with severe traumatic brain injury (TBI) support the use of hypertonic sodium lactate infusions. Administration of lactate salts acts as an osmotic agent to reduce elevated intracranial pressure and brain swelling, provides an alternative aerobic energy substrate ('fuel') that spares cerebral glucose utilization, and serves as an alkalinizing buffer through hepatic conversion of lactate to bicarbonate.

0:23:32Rhonda Patrick (host)supportedhigh

Brain-derived neurotrophic factor (BDNF) stimulates the generation and growth of new brain cells.

"In terms of BDNF, which is a neurotrophic factor, it actually stimulates the growth of new brain cells." (said at 0:23:32)

Brain-derived neurotrophic factor (BDNF) is an established neurotrophic factor that binds to tropomyosin receptor kinase B (TrkB) to promote neurogenesis, neuronal differentiation, maturation, and survival in both developing and adult mammalian brains.

0:30:11George Brookssupportedlow

Infusing lactate in patients with traumatic brain injury increases total cerebral carbohydrate uptake (glucose plus lactate).

"And we actually have done six patients, in collaboration with our colleagues at UCLA. We show that we can increase the carbohydrate uptake, that is the total of glucose plus lactate, in people with brain injury by infusing lactate." (said at 0:30:11)

Collaborative metabolic tracer and infusion studies conducted in human traumatic brain injury (TBI) patients by researchers at UCLA and UC Berkeley demonstrate that exogenous sodium L-lactate infusion increases net cerebral carbohydrate uptake. In these studies, infusing L-lactate changed cerebral metabolism from net lactate release to net lactate uptake (as measured by arteriovenous differences and isotopic tracers) while systemic glucose availability was maintained, resulting in increased total brain carbohydrate uptake (glucose plus lactate). The GRADE certainty is low due to the small sample sizes typical of intensive metabolic catheterization and tracer studies.

0:34:50George Brookssupportedmoderate

D-lactate is neurotoxic.

"And D-lactate is actually neurotoxic." (said at 0:34:50)

Elevated D-lactate is well established in clinical literature and animal studies as causing neurotoxicity and metabolic encephalopathy (frequently termed D-lactate encephalopathy or D-lactic acidosis). Unlike L-lactate, excessive systemic accumulation of D-lactate crosses the blood-brain barrier and directly induces central nervous system impairment, manifesting as ataxia, confusion, delirium, and slurred speech.

0:35:22George Brookssupportedhigh

Lactated Ringer's solution was historically prepared as a 50/50 racemic mixture of D-lactate and L-lactate.

"And so what was available was lactate, and he tried it and it seemed to work, but at that time it was a 50/50 mixture." (said at 0:35:22)

Published pharmacological and medical literature confirms that lactated Ringer's solution has historically and conventionally been prepared with racemic lactate, which is an equimolar (50/50) mixture of the D- and L-stereoisomers.

0:36:22George Brookssupportedhigh

Monocarboxylate transporters transport ketones, pyruvate, and lactate.

"realize that the lactate transporters also transport ketones and pyruvate as well as lactate." (said at 0:36:22)

Monocarboxylate transporters (MCTs, notably MCT1–4 of the SLC16 family), commonly referred to as lactate transporters, mediate the proton-coupled transport of monocarboxylates across cell membranes, specifically transporting L-lactate, pyruvate, and ketone bodies (such as acetoacetate and β-hydroxybutyrate).

0:36:53George Brookssupportedhigh

Monocarboxylate transporters are saturable, meaning all-lactate can block ketone transport and all-ketones can block lactate transport.

"The thing about it, and once you realize that they are transporters and understand how they perform, they're saturable. So if we have an all-lactate, then that'll probably block ketones, and if we have all ketones, that'll block lactate." (said at 0:36:53)

Monocarboxylate transporters (MCTs 1–4, encoded by SLC16 family genes) are carrier-mediated, proton-linked transporters that follow saturable Michaelis-Menten kinetics. They share substrate specificity across aliphatic monocarboxylates, including L-lactate, pyruvate, and the ketone bodies (acetoacetate and β-hydroxybutyrate). Because these substrates utilize the same binding and translocation mechanisms, high concentrations of one substrate (such as lactate) competitively inhibit and saturate the transporter, reducing or blocking the transport of other substrates (such as ketone bodies), and vice versa.

0:37:55George Brookssupportedlow

L-lactate uptake shows saturation kinetics, whereas D-lactate uptake is linear and occurs by diffusion without sharing the transporter.

"no, they don't share the transporter. So actually one of the tests we did early on, we showed a saturation kinetics with L-lactate, and D comes in in a linear fashion, so it probably comes in simply by diffusion. So fortunately, it doesn't share the transporter" (said at 0:37:55)

Transport studies in rat skeletal muscle sarcolemmal vesicles confirm that L-lactate uptake shows saturable Michaelis-Menten kinetics, whereas D-lactate uptake remains linear across a broad concentration range (1 to 200 mM) and does not substantially compete with or share the L-lactate transporter, indicating entry by simple diffusion.

0:38:57George Brookssupportedhigh

The intestinal lactate transporter belongs to a different gene family than the monocarboxylate transporters in cell membranes and functions as a sodium symport rather than a proton symport.

"there was an intestinal transporter, a lactate transporter, so a different gene family than the one that's in the cell membranes. And what's neat about it is it's sodium-mediated, it's not proton—it's not a symport for protons, it's a symport for sodium." (said at 0:38:57)

The claim is accurate. Classic plasma membrane monocarboxylate transporters (MCTs 1-4) belong to the SLC16 gene family and function as proton-coupled symporters (H+-dependent). In contrast, the intestinal monocarboxylate/lactate transporters SMCT1 (SLC5A8) and SMCT2 (SLC5A12) belong to the SLC5 gene family (the solute carrier family 5, which includes sodium/glucose cotransporters) and function as sodium-coupled symporters (Na+-dependent) rather than proton symporters.

0:39:28George Brookssupportedhigh

The glucose transporter in the intestinal tract is sodium-mediated, allowing glucose with salt to be absorbed faster than glucose alone.

"And also the glucose transporter in the intestinal tract is a sodium-mediated one. So, you know, how these sports drinks really work very well and work better than water regardless of the brand, because if you have glucose and a pinch of salt, it's going to get in faster than glucose alone." (said at 0:39:28)

Intestinal glucose uptake across the apical brush border membrane of enterocytes is primarily mediated by the sodium-dependent glucose cotransporter 1 (SGLT1, encoded by SLC5A1). SGLT1 operates as an electrogenic symporter, coupling the transport of two sodium ions down their electrochemical gradient to drive the transport of one glucose molecule into the enterocyte. The presence of luminal sodium is physiologically necessary for SGLT1-mediated glucose cotransport, which underlies both the rapid absorption of glucose in electrolyte-containing beverages and the therapeutic efficacy of oral rehydration solutions.

0:41:41George Brookssupportedvery low

In isolated sarcolemmal vesicles, lactate outcompetes ketones, glucose, and amino acids for transporter uptake because it fits the transporter configuration better.

"The first studies we did in 1990 where we did isolated sarcolemmal vesicles... And so that's how we described the lactate transporter, is we compared it to glucose and amino acids and to ketones, and so lactate is preferred to get in, right? It outcompetes because it really fits the transporter configuration better than the other things do." (said at 0:41:41)

In a 1990 study evaluating isolated rat skeletal muscle sarcolemmal membrane vesicles, Roth and Brooks characterized the kinetics and substrate specificity of the membrane-bound monocarboxylate/lactate carrier. They demonstrated that 1 mM L(+)-lactate uptake was strongly inhibited by excess unlabeled L(+)-lactate (82%) and pyruvate (71%), but only moderately inhibited by ketone bodies (27% by beta-hydroxybutyrate, 32% by acetoacetate), and not effectively inhibited by a 10-fold excess of amino acids (alanine, aspartate, glutamate) or other non-target substrates, confirming carrier specificity and preference for lactate and pyruvate over ketones and amino acids. Because this evidence comes from in vitro animal vesicle preparations, the certainty is graded as very low.

  • supports: Lactate transport is mediated by a membrane-bound carrier in rat skeletal muscle sarcolemm… (Archives of biochemistry and biophysics 1990) · cited 181x in the literature
    "Furthermore, unlabeled 10 mM D(-)-lactate in the external medium could only inhibit 1 mM isotopic (L(+) uptake by 12%, whereas unlabeled 10 mM L(+)-lactate and pyruvate inhibited 82 and 71%, respectively. Additionally, 10 mM beta-hydroxybutyrate and acetoacetate could moderately inhibit (27 and 32%, respectively) 1 mM L(+)-lactate transport, but the unsubstituted aliphatic monocarboxylates (formate, acetate, propionate), tricarboxylic acid cycle intermediates (malate, succinate, oxaloacetate, alpha-ketoglutyrate, citrate), amino acids (alanine, aspartate, glutamate), and palmitate or adenosine in 10-fold excess could not effectively inhibit 1 mM L(+)lactate uptake under cis-transport conditions." (abstract, results, passage verified)
    pubmedfull study (doi)
0:45:16George Brookssupportedmoderate

During exercise in men, infused or elevated blood lactate is metabolized preferentially over glucose by muscle, heart, and brain.

"because we've given lactate to men during exercise and it is preferred over glucose, and— In muscle, heart... Now, and also in brain." (said at 0:45:16)

Physiological tracer and infusion studies in humans demonstrate that when blood lactate concentrations are elevated (such as during exercise or via exogenous infusion), lactate is readily cleared and oxidized as a preferred fuel source relative to glucose by oxidative skeletal muscle fibers, the myocardium (heart), and the brain, down-regulating alternative substrate utilization.

0:45:23George Brookssupportedmoderate

Glucose metabolism and utilization in the brain are impaired following traumatic brain injury.

"But after traumatic brain injury, when the ability to use glucose is blocked, then we can supplement by giving lactate." (said at 0:45:23)

Traumatic brain injury (TBI) induces significant cerebral metabolic dysregulation, marked by disruptions in glucose processing, metabolic crisis, and impaired energy production. Research demonstrates that exogenous lactate (typically administered as hypertonic sodium lactate infusions) can serve as an alternative energy substrate for the injured brain, sparing glucose, improving neuroenergetics, reducing intracranial pressure, and supporting cerebral metabolism.

0:45:47George Brookssupportedhigh

Lactate is more reduced and contains more chemical energy than pyruvate.

"It's more reduced, so it actually has more energy than pyruvate." (said at 0:45:47)

Lactate is the reduced form of pyruvate, formed when lactate dehydrogenase catalyzes the transfer of two electrons and a proton from NADH to pyruvate (Pyruvate + NADH + H⁺ ⇌ Lactate + NAD⁺). Because lactate contains two additional electrons (reducing equivalents) compared to pyruvate's oxidized ketone group, it is in a more reduced state and has a higher chemical energy content (enthalpy of combustion). When lactate is oxidized back to pyruvate in oxidative tissues, the transferred reducing equivalent generates NADH, which yields additional ATP through the mitochondrial electron transport chain.

  • supports: Lactate as a fulcrum of metabolism. (Redox biology 2020) · cited 727x in the literature
    "By shuttling between producer (driver) and consumer (recipient) cells lactate fulfills at least three purposes: 1] a major energy source for mitochondrial respiration; 2] the major gluconeogenic precursor; and 3] a signaling molecule. Working by mass action, cell redox regulation, allosteric binding, and reprogramming of chromatin by lactylation of lysine residues on histones, lactate has major influences in energy substrate partitioning." (abstract, passage verified)
    pubmedfull study (doi)
0:46:18George Brookssupportedlow

Neurons possess all the intact molecular apparatus necessary to take up glucose and produce lactate.

"But Rasha Hussien, who just poked her head in here, she has a paper where she showed that all the apparatus for neurons to take glucose and make lactate are intact always." (said at 0:46:18)

Preclinical biochemical and immunohistochemical studies by Hussien and Brooks demonstrated that neurons express key molecular components required for monocarboxylate transport and lactate metabolism, including monocarboxylate transporter isoforms (MCT1, MCT2) and lactate dehydrogenase (LDH) localized with neuronal mitochondria. These findings demonstrate that neurons possess the intact molecular machinery to participate in intracellular and cell-to-cell lactate transport and oxidation alongside standard glucose metabolism.

0:47:11George Brookssupportedmoderate

Traumatic brain injury exhibits a bimodal age distribution, occurring most frequently in young men and in older adults of both sexes.

"So there's sort of a bimodal distribution of traumatic brain injury: the young men and then people of both genders later in life." (said at 0:47:11)

Epidemiological studies of traumatic brain injury (TBI) consistently document distinct incidence peaks across the lifespan. TBI incidence is heavily skewed toward young males during adolescence and early adulthood (largely due to motor vehicle collisions, sports, and violence) and rises again sharply in older adults of both sexes (primarily resulting from falls). While some classifications describe a trimodal distribution when including early childhood (ages 0-4), the pattern across youth and older adulthood is widely recognized as bimodal.

0:48:45Rhonda Patrick (host)supportedvery low

In worm and mouse models of Parkinson's disease, lactate administration enhances mitochondrial function and increases cell viability.

"a study came out in worms and also a mice Parkinson's model—worms don't actually have a brain, but they do have Parkinson's models for worms where they have alpha-synuclein, which is one of the toxic proteins that aggregates in Parkinson's disease. They have these worms making that at an accelerated rate, but they showed that feeding the worms lactate helped improve the mitochondrial function, it increased the cell viability, and also in mice." (said at 0:48:45)

Preclinical evidence demonstrates that lactate administration can stimulate mitophagy, improve mitochondrial clearance, and protect cell viability in experimental models of Parkinson's disease, including alpha-synuclein and Pink1 mutation models, as well as ex vivo mouse brain tissue. Because these findings are derived entirely from cell cultures, invertebrate models, and animal tissue, the evidence is rated as very low certainty regarding clinical outcomes in humans.

  • supports: Metabolically induced intracellular pH changes activate mitophagy, autophagy, and cell pro… (The FEBS journal 2022) · cited 44x in the literature
    "Here, we used sodium pyruvate and sodium lactate to induce changes in intracellular pH in human fibroblasts with PD mutations (Pink1, Pink1/Park2, α-synuclein triplication, A53T). We have found that both lactate and pyruvate in millimolar concentrations can induce a short-time acidification of the cytosol in these cells. This induced activation of mitophagy and autophagy in control and PD fibroblasts and protected against cell death. Importantly, application of lactate to acute brain slices of WT and Pink1 KO mice also induced a reduction of pH in neurons and astrocytes that increased the level of mitophagy." (abstract, results, passage verified)
    pubmedfull study (doi)
0:54:48George Brookssupportedmoderate

During exercise, elevated blood lactate substitutes for glucose as an energy source in the brain.

"a group from Copenhagen showed that when you exercise and your blood lactate rises, it substitutes for glucose in the brain." (said at 0:54:48)

Seminal human physiological studies led by researchers at the University of Copenhagen (such as Dalsgaard, Secher, and Quistorff) demonstrated that during high-intensity or exhaustive exercise, elevated arterial lactate is taken up by the brain in substantial quantities and oxidised as fuel rather than accumulating. Subsequent human arterio-venous catheterization studies have confirmed that as circulating lactate rises (whether through exercise or exogenous infusion), the brain shifts to preferentially oxidise lactate, resulting in a dose-dependent reduction in cerebral glucose uptake and oxidation.

0:55:41George Brookssupportedhigh

Pyruvate degrades spontaneously in aqueous solution, forming toxic degradation products.

"early on it was recognized that pyruvate degrades in solution, makes toxic products. So others have tried to keep a crystalline pyruvate on hand and mix it up in saline right away and then give that at high levels." (said at 0:55:41)

The claim is supported. In aqueous solutions, pyruvate spontaneously undergoes an aldol-like condensation dimerization reaction to form 2-hydroxy-2-methyl-4-ketoglutaric acid (parapyruvate). Parapyruvate is biologically toxic because it acts as a potent inhibitor of the alpha-ketoglutarate dehydrogenase complex within the mitochondrial tricarboxylic acid (Krebs) cycle, impairing cellular respiration and inducing cellular senescence. Because of this chemical instability in solution, investigators and manufacturers have historically needed to use freshly prepared solutions or stable derivatives (such as ethyl pyruvate).

Unverified means no publication matching the claim was located; it does not prove the claim false. Spotted an error? See the corrections policy - disputes from the people quoted are prioritized.