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FoundMyFitness · 2022-04-28 · Rhonda Patrick (host), Dominic D'Agostino

Dr. Dominic D'Agostino on Developing a Well-Designed Ketogenic Diet and Harnessing Its Benefits

85 research-tied claims examined: 1 contradicted 5 overstated 6 context 60 supported 1 corroborated online 12 unverified

60

Supported by research

0:00:00Dominic D'Agostinosupportedhigh

The caloric density of a ketogenic diet is approximately 50% higher than a standard diet.

"the caloric density of the ketogenic diet is like 50% higher, so you can't eat—" (said at 0:00:00)

The claim is supported by controlled clinical data evaluating the composition and energy density of ketogenic diets compared to low-fat or standard diets. In a landmark randomized crossover trial led by Hall et al. (2021) at the National Institutes of Health (PMID 33479499), the energy density of the animal-based ketogenic diet (~2.0 kcal/g) was roughly double (over 100% higher, and at least 50% higher) compared to the low-fat comparator diet (~0.9 to 1.1 kcal/g) due to its high fat content (75.8% fat vs. 10.3% fat). Because fat contains 9 kcal/g compared to 4 kcal/g for carbohydrates and protein, ketogenic diets inherently possess a significantly higher caloric density per unit mass than carbohydrate-rich standard diets.

0:02:07Dominic D'Agostinosupportedhigh

A classical 4:1 ketogenic diet consists of 90% fat and one part protein and carbohydrates combined.

"from a 4:1, which is a classical ketogenic diet, which is 90% fat and one part protein and carbohydrates" (said at 0:02:07)

The speaker accurately defines the classical 4:1 ketogenic diet. In clinical nutrition and epilepsy management, the classical ketogenic diet is formulated as a 4:1 ratio by weight of fat to combined protein and carbohydrates (4 grams of fat for every 1 gram of protein plus carbohydrate). Because fat provides 9 kcal/g and carbohydrates/protein provide 4 kcal/g, this 4:1 gram ratio corresponds directly to 90% of total energy (calories) derived from fat and 10% from protein and carbohydrates combined.

0:04:38Dominic D'Agostinosupportedhigh

Fasting suppresses insulin and depletes liver glycogen, accelerating beta-oxidation of fatty acids in the liver to produce acetyl-CoA, which condenses into acetoacetate and beta-hydroxybutyrate.

"So when you fast, you suppress the hormone insulin, you deplete liver glycogen, and then that accelerates beta-oxidation of fatty acids. And it's the oxidation of fatty acids in the liver, or the over-oxidation of fatty acids, that accelerates production of acetyl-CoA, and then that condenses to acetoacetate and beta-hydroxybutyrate." (said at 0:04:38)

The speaker accurately describes the well-established biochemical pathway of fasting-induced ketogenesis. During fasting, decreased insulin and depletion of hepatic glycogen lead to increased lipolysis and accelerated mitochondrial beta-oxidation of fatty acids in the liver. This elevates hepatic acetyl-CoA, which condenses to form acetoacetate and is subsequently converted into beta-hydroxybutyrate.

0:07:50Dominic D'Agostinosupportedmoderate

Dr. Eric Kossoff and Dr. John Freeman published research around 2007 or 2008 establishing that the modified Atkins diet can effectively treat epilepsy in adults.

"I think in 2008 Dr. Eric Kossoff from Johns Hopkins, he worked with Dr. John Freeman, the late John Freeman, and developed a modified Atkins diet or modified ketogenic diet for adult epilepsy. And then it was published that the diet can work for adults too back in 2007 or '8, I think around that time." (said at 0:07:50)

In 2008, Dr. Eric Kossoff and colleagues at Johns Hopkins published a prospective clinical study evaluating the modified Atkins diet in adults with intractable epilepsy (Epilepsia, 2008). In the intention-to-treat analysis of 30 adult patients, 47% achieved greater than 50% seizure reduction at 1 and 3 months, establishing that the modified Atkins diet can be effective for adult refractory epilepsy.

0:20:30Dominic D'Agostinosupportedmoderate

Consuming large amounts of whey protein stimulates an insulin response driven by essential and branched-chain amino acids that suppresses ketosis.

"But taking a big hit of protein, like drinking whey protein, will kick you out of ketosis because you're going to get the insulin response from the essential amino acids, and branched-chain amino acids, too, can increase that." (said at 0:20:30)

Whey protein is rich in essential amino acids (EAAs) and branched-chain amino acids (BCAAs), particularly leucine, isoleucine, and valine, which act directly on pancreatic beta-cells and stimulate incretin hormones (such as GIP and GLP-1) to induce acute insulin secretion. Because insulin is the primary physiological suppressor of lipolysis and hepatic ketogenesis, large boluses of rapidly absorbed insulinogenic proteins like whey stimulate an insulin surge that transiently suppresses ketone body production.

0:21:40Dominic D'Agostinosupportedhigh

A ketogenic diet is medically contraindicated in patients with carnitine palmitoyltransferase deficiency (CPT-1 deficiency) and can be fatal.

"And interestingly, there are inborn errors of metabolism that are contraindicated with a ketogenic diet, like carnitine transferase activity, CPT-1, whether it be primary or secondary, too. So it could be deadly; a ketogenic diet could potentially kill you if you have carnitine transferase deficiency." (said at 0:21:40)

Published clinical guidelines and reviews on ketogenic dietary therapies identify disorders of fatty acid oxidation and carnitine transport/metabolism (such as carnitine palmitoyltransferase deficiencies and primary carnitine deficiency) as absolute contraindications. Because a ketogenic diet relies heavily on the transport and mitochondrial beta-oxidation of fatty acids to produce energy and ketone bodies, placing individuals with these inborn errors of metabolism on a high-fat, carbohydrate-restricted regimen impairs energy production and can trigger severe metabolic decompensation, hypoketotic hypoglycemia, hepatic failure, and life-threatening outcomes.

0:26:00Dominic D'Agostinosupportedvery low

Poorly formulated ketogenic diets have led to selenium deficiency and fatal cardiomyopathy in published case reports.

"As you know, there's been a lack of appreciation for micronutrients in ketogenic diets, and that has caused problems like selenium deficiency, which led to cardiomyopathy. And there's case reports where people have literally—I think one or two—where people have literally died from cardiomyopathy because of selenium deficiency associated with the ketogenic diet." (said at 0:26:00)

Published case reports document that unsupplemented or poorly formulated ketogenic diets used for intractable epilepsy can lead to severe selenium deficiency and secondary cardiomyopathy, including fatal outcomes. A 2008 case report series documented two pediatric deaths associated with selenium deficiency and cardiac complications while on a ketogenic diet, with post-mortem examination in one case confirming selenium-deficiency cardiomyopathy. Other case reports describe non-fatal reversible cardiomyopathy and ventricular arrhythmias triggered by selenium deficiency on ketogenic regimens, which resolved upon selenium repletion and dietary adjustment. Because this evidence consists of individual case reports and case series, the certainty is very low.

0:27:02Dominic D'Agostinosupportedmoderate

A clinical trial evaluating the caprylic triglyceride supplement AC-1202 in Alzheimer's disease found cognitive improvements correlated with ketone levels, but this correlation was absent in APOE4 carriers.

"There is a study that was done using a product that is caprylic triglyceride, which is MCT. At the time it was called AC-1202 by Accera. It was a product that was designed for Alzheimer's disease as an alternative energy substrate that would be given, and the results of the study showed that improvements in mild cognitive impairment were associated with ketones, so there was a correlation with that. But they did not see the correlation in people with APOE4" (said at 0:27:02)

A 90-day double-blind, randomized, placebo-controlled trial of AC-1202 (a caprylic triglyceride formulation) in 152 patients with mild-to-moderate Alzheimer's disease found that cognitive improvement (measured by the ADAS-Cog score) was significantly correlated with serum beta-hydroxybutyrate (ketone) levels at Day 90 in APOE4-negative subjects (p = 0.008), whereas this therapeutic effect and correlation were not observed in APOE4 carriers.

0:06:25Dominic D'Agostinosupportedmoderate

Low glycemic index therapy produces an anti-seizure therapeutic effect despite producing little to no elevation in blood ketones.

"Then something like a low glycemic index diet, which can produce little or no ketones, it can still have an anti-seizure effect and still have benefits even independent of high ketones." (said at 0:06:25)

The low-glycemic-index treatment (LGIT) allows a more liberal carbohydrate intake (restricted to foods with a glycemic index < 50) and achieves substantial seizure reduction in patients with drug-resistant epilepsy, even though it produces only mild to minimal ketosis compared to traditional ketogenic diets. Clinical evaluations and reviews confirm that antiepileptic efficacy does not strictly correlate with high systemic ketone levels across all dietary therapies.

0:15:30Rhonda Patrick (host)supportedhigh

Dietary fiber is fermented by the gut microbiota into butyrate, which fuels and provides energy to colonocytes.

"because the other thing is that with fiber, you are making butyrate in the gut when you're—or your bacteria is making it, the microbiome inside your gut, and that is fueling the colonocytes, right, giving them energy." (said at 0:15:30)

The speaker's statement accurately reflects a well-established principle of human gastrointestinal physiology. Dietary fiber and resistant starches that escape digestion in the upper gastrointestinal tract are fermented by anaerobic gut bacteria (primarily within the phylum Firmicutes) into short-chain fatty acids, predominant among which is butyrate. Colonocytes utilize butyrate as their primary energy substrate, deriving the majority of their cellular energy requirements via its oxidation.

0:20:10Dominic D'Agostinosupportedmoderate

Ingesting high doses of exogenous ketones can stimulate insulin secretion.

"Exogenous ketones can actually increase insulin if it's too much, and we can talk about the different variations of that and why that could be problematic in some conditions." (said at 0:20:10)

The speaker claims that ingesting exogenous ketones can stimulate insulin secretion. This statement is supported by clinical trials and literature reviews on exogenous ketone administration and ketone body signaling. In a clinical trial involving healthy males, oral ingestion of D/L-3-hydroxybutyrate directly increased circulating insulin and C-peptide levels compared to intravenous administration (PMID: 32717058). A 2025 review on ketone bodies and glucose metabolism also notes that recent research confirms the insulin-stimulatory effect of ketones in pancreatic islets, animal models, and human participants, depending on the metabolic context and glucose availability (PMID: 40585886). Under certain oral glucose tolerance test conditions, ketone monoester supplementation enhanced early-phase insulin release in individuals with impaired glucose tolerance (PMID: 33010116).

0:21:30Dominic D'Agostinosupportedhigh

The ketogenic diet is a medically established and accepted treatment for glucose transporter type 1 deficiency syndrome and pyruvate dehydrogenase deficiency.

"It remains the only widely accepted application of the ketogenic diet at this time is really epilepsy and metabolic disorders like glucose transporter type 1 deficiency syndrome, PDH deficiency, and things like that." (said at 0:21:30)

The ketogenic diet is an established and standard clinical treatment for rare inborn errors of metabolism that impair cerebral glucose metabolism, specifically glucose transporter type 1 (GLUT1) deficiency syndrome and pyruvate dehydrogenase (PDH) complex deficiency. In these conditions, ketone bodies serve as an alternative energy substrate for the brain, bypassing defective glucose transport across the blood-brain barrier (in GLUT1 deficiency) or impaired glycolysis-to-TCA cycle conversion (in PDH deficiency).

0:23:55Dominic D'Agostinosupportedmoderate

Approximately 25% of the human population carries an APOE4 allele.

"So ApoE4, that's about one-quarter, right, of the population." (said at 0:23:55)

Population genetics and epidemiological surveys indicate that approximately 20% to 25% of the general population (particularly in European and American cohorts) carries at least one APOE ε4 allele (carrier frequency), although the exact frequency varies geographically and across ancestral populations (e.g., lower in East Asian populations and higher in certain African and Indigenous populations). The speaker's statement that about one-quarter of the population carries an APOE4 allele is consistent with established population genetic data.

0:28:00Dominic D'Agostinosupportedvery low

A published case report documented an Alzheimer's disease patient who experienced cognitive and behavioral improvements after treatment with ketone esters and exogenous ketone supplementation.

"There was a case report on a patient that I am familiar with, that I'm familiar with with the wife of the patient that had passed away. But he was maintained on a ketogenic diet and then later on ketone esters and exogenous ketones, and did quite well on this diet for a long time. And it wasn't a restrictive ketogenic diet, but he did much better with ketone supplementation as a means to improve his cognition and different behavioral parameters too." (said at 0:28:00)

A published case report (Newport et al., 2015) documented the use of oral ketone monoester (KME) supplementation over a 20-month period in an Alzheimer's disease dementia patient (baseline MMSE score of 12). The report documented marked improvements in mood, affect, self-care, daily activity performance, and cognitive performance that tracked with plasma beta-hydroxybutyrate levels without requiring a restrictive ketogenic diet. Because this evidence is derived entirely from a single uncontrolled case report, the certainty of evidence for clinical efficacy is very low.

0:33:31Dominic D'Agostinosupportedhigh

During ketosis, the brain metabolizes both glucose and ketones rather than completely stopping glucose utilization, while blood glucose is maintained near normal and insulin drops.

"So your brain is switching from using glucose and pretty much only glucose to using glucose and ketones. It never switches completely off of glucose and ketones. So the homeostatic mechanisms that maintain your blood glucose are very powerful, so your glucose pretty much stays normal, but insulin goes down." (said at 0:33:31)

Classic human metabolic studies and extensive clinical literature establish that during prolonged ketosis (such as during fasting or a ketogenic diet), ketone bodies (beta-hydroxybutyrate and acetoacetate) become the predominant fuel for cerebral energy metabolism, displacing but not completely replacing glucose utilization. Throughout this adaptation, hepatic gluconeogenesis and glycogenolysis maintain blood glucose concentrations within a closely regulated homeostatic range while basal circulating insulin levels decline substantially.

0:33:58Dominic D'Agostinosupportedmoderate

Ketone bodies function as signaling molecules that elevate adenosine and activate the GPR109A receptor.

"So we produce these endogenous metabolites, and they not only serve as alternative energy for the brain and the heart and other tissues, but then they have signaling effects that mediate many of the beneficial effects associated with being in a state of therapeutic ketosis. So that's things like elevating adenosine, activating various ketone receptors—GPR109A receptor, for example—anti-inflammatory pathways." (said at 0:33:58)

Ketone bodies, particularly beta-hydroxybutyrate (β-OHB), are well-established to function both as energy substrates and as signaling molecules. β-OHB acts as an endogenous ligand and agonist for the G-protein-coupled receptor GPR109A (also known as hydroxycarboxylic acid receptor 2, HCAR2), through which it exerts anti-inflammatory and metabolic effects. Furthermore, ketosis and ketogenic interventions have been shown to elevate extracellular and tissue levels of adenosine, which mediates neuromodulatory and anticonvulsant effects primarily via adenosine A1 receptors.

0:34:40Dominic D'Agostinosupportedvery low

Beta-hydroxybutyrate and ketone molecules reduce mitochondrial reactive oxygen species (ROS) and superoxide anion production.

"we measured like superoxide anion production using ethidium molecule, like the fluorescence, and showed that mitochondrial ROS production goes down with beta-hydroxybutyrate and ketone molecules." (said at 0:34:40)

Preclinical laboratory research supports the claim that beta-hydroxybutyrate and ketone supplementation reduce superoxide anion and reactive oxygen species (ROS) production. Specifically, in ex vivo rat brainstem slices exposed to hyperoxia, researchers measured cellular superoxide production using the fluorogenic dye dihydroethidium (DHE) and demonstrated that co-exposure to ketone salts containing beta-hydroxybutyrate and acetoacetate significantly blunted the increase in DHE fluorescence, reflecting reduced superoxide generation. Because the supporting evidence derives from animal tissue-slice models, the GRADE certainty for broader human biological translation is very low.

0:35:39Dominic D'Agostinosupportedhigh

GABA is synthesized from glutamate via glutamic acid decarboxylase, while glutamate is an excitatory neurotransmitter that activates AMPA and NMDA receptors.

"So GABA is made from glutamate via an enzyme called glutamic acid decarboxylase. So glutamate is the most ubiquitous neurotransmitter in the system, in our body, and that's an excitatory neurotransmitter that activates the AMPA receptors and NMDA receptors." (said at 0:35:39)

The statement accurately describes established neurochemical pathways and neurotransmitter functions. Gamma-aminobutyric acid (GABA) is synthesized from glutamate via the enzyme glutamate decarboxylase (glutamic acid decarboxylase / GAD). Glutamate is the primary excitatory neurotransmitter in the central nervous system and acts via ionotropic glutamate receptors, including AMPA and NMDA receptors.

0:36:14Dominic D'Agostinosupportedvery low

In a mouse model of Angelman syndrome, administration of a ketone ester on a standard diet increased GAD65, GAD67, and GABA levels, improving learning and memory and producing anti-anxiety effects.

"We had an animal model of Angelman syndrome, and we administered ketone ester with a standard diet and saw an increase in GAD65 and 67 and essentially an increase in GABA. And then that resulted in what we saw: increase in learning, memory; we saw, you know, anti-anxiety effects; and the increase in GABAergic tone likely contributes to the anti-seizure effect of that." (said at 0:36:14)

In a preclinical study using an Angelman syndrome mouse model, ad libitum administration of a ketone ester (R,S-1,3-butanediol acetoacetate diester) along with standard diet improved learning, memory, synaptic plasticity, motor function, and behavioral measures while exerting anticonvulsant effects and altering brain amino acid metabolism. Because this evidence relies exclusively on an animal model, the certainty for clinical efficacy in humans is very low.

0:36:45Dominic D'Agostinosupportedhigh

Vigabatrin is an anti-seizure medication that acts through GABAergic mechanisms.

"And many anti-seizure drugs, like vigabatrin and other drugs, work through GABA." (said at 0:36:45)

Vigabatrin is an established antiseizure medication that acts directly on the GABAergic system. It functions as an irreversible inhibitor of GABA aminotransferase (GABA-T), the enzyme responsible for catabolizing gamma-aminobutyric acid (GABA), thereby elevating brain GABA levels and enhancing inhibitory neurotransmission to suppress seizures.

0:40:41Dominic D'Agostinosupportedvery low

Combining ketone salts with medium-chain triglycerides delays gastric absorption and extends hyperketonemia duration.

"If you take ketone salts and you combine it with medium-chain triglycerides, the fat delays gastric absorption and pushes the pharmacokinetic curve, if you will, to the right. So you get—and this is important—you get a little bit slower elevation of blood ketones, and then you have a significant sustainment of hyperketonemia over time and the decrease in the spike." (said at 0:40:41)

Preclinical pharmacokinetic studies evaluating exogenous ketone supplements (such as a 1:1 mixture of beta-hydroxybutyrate mineral salts and medium-chain triglyceride oil) demonstrate that co-administration moderates the initial peak in blood beta-hydroxybutyrate levels and prolongs the duration of elevated blood ketones compared to ketone mineral salts administered alone. However, this specific pharmacokinetic profile has primarily been characterized in preclinical animal models.

0:45:36Dominic D'Agostinosupportedvery low

The glycolytic inhibitor 2-deoxyglucose exerts anti-seizure effects at approximately 25 mg/kg, but becomes cardiotoxic at higher doses.

"2-deoxyglucose has a pretty strong anti-seizure effect, and that is being advocated and used clinically in some studies as the ketogenic diet in a drug, so a glycolytic inhibitor, 2-deoxyglucose. So you consume this drug, and it's like 25 milligrams per kilogram, and if you go higher than that, then it becomes cardiotoxic, so it's not an ideal approach." (said at 0:45:36)

Preclinical studies support that the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) possesses anticonvulsant and anti-seizure properties in animal models. However, its therapeutic window is limited because chronic administration of 2-DG at higher doses induces cardiotoxicity, including dose-dependent cardiac myocyte vacuolization, increased mortality, and other adverse effects in rodents. Evidence for its anti-seizure effects and dose-limiting cardiotoxicity is derived primarily from preclinical animal models rather than established human clinical trials.

0:51:00Dominic D'Agostinosupportedhigh

1,3-butanediol is metabolized in the liver primarily into beta-hydroxybutyrate.

"So it's 1,3-butanediol, which gets metabolized in the liver completely, pretty much, to beta-hydroxybutyrate." (said at 0:51:00)

The claim that 1,3-butanediol is metabolized primarily in the liver into beta-hydroxybutyrate is well-supported by biochemistry and empirical studies. In human and animal liver preparations, 1,3-butanediol ((R)-1,3-BD) undergoes hepatic oxidation via alcohol dehydrogenase and aldehyde intermediates to produce (R)-beta-hydroxybutyrate (BHB). Tissue-comparative studies demonstrate that the liver is the primary site responsible for converting 1,3-butanediol to beta-hydroxybutyrate, accounting for systemic ketone elevation following administration.

0:52:34Dominic D'Agostinosupportedvery low

In an animal model of tonic-clonic seizures induced by hyperbaric oxygen, 1,3-butanediol acetoacetate diester increased the latency to seizure by 600%.

"The 1,3-butanediol acetoacetate diester elevates beta-hydroxybutyrate and acetoacetate more or less in a one-to-one ratio... And and we had a 600% increase in the latency to seizure, which means that animals could go 600% longer. And we published that." (said at 0:52:34)

A 2013 study in adult rats exposed to 5 atmospheres absolute of hyperbaric oxygen found that oral administration of R,S-1,3-butanediol acetoacetate diester rapidly elevated beta-hydroxybutyrate and acetoacetate to equimolar concentrations (>3 mM each) and increased latency to tonic-clonic seizure by 574 ± 116% (approximately 600%) relative to water controls. Because this evidence comes entirely from an animal model, the certainty for human clinical application is rated very low.

0:56:35Dominic D'Agostinosupportedmoderate

1,3-butanediol is metabolized in the liver via the alcohol dehydrogenase pathway.

"the 1,3-butanediol is also a consideration, right, because the liver has to work harder, so it uses the alcohol dehydrogenase pathway." (said at 0:56:35)

1,3-butanediol is metabolized in the liver to ketone bodies (primarily β-hydroxybutyrate) via the alcohol dehydrogenase (ADH) pathway. Animal and hepatic tissue studies demonstrate that hepatic ADH oxidizes 1,3-butanediol into an intermediate aldehyde (3-hydroxybutanal/aldol), which is subsequently converted by aldehyde dehydrogenase into β-hydroxybutyrate. Inhibiting ADH with 4-methylpyrazole substantially reduces the elimination rate of 1,3-butanediol, confirming ADH's central role in its hepatic metabolism.

  • supports: Contribution of liver alcohol dehydrogenase to metabolism of alcohols in rats. (Chemico-biological interactions 2015) · cited 42x in the literature
    "The kinetics of oxidation of various alcohols by purified rat liver alcohol dehydrogenase (ADH) were compared with the kinetics of elimination of the alcohols in rats in order to investigate the roles of ADH and other factors that contribute to the rates of metabolism of alcohols. Primary alcohols (ethanol, 1-propanol, 1-butanol, 2-methyl-1-propanol, 3-methyl-1-butanol) and diols (1,3-propanediol, 1,3-butanediol, 1,4-butanediol, 1,5-pentanediol) were eliminated in rats with zero-order kinetics at doses of 5-20 mmol/kg... The rates of elimination of various alcohols were inhibited on average 73% (55% for 2-propanol to 90% for ethanol) by 1 mmol/kg of 4-methylpyrazole, a good inhibitor of ADH, indicating a major role for ADH in the metabolism of the alcohols." (abstract, results, passage verified)
    pubmedfull study (doi)
  • supports: Characterizing the Hepatic Metabolic Pathway of Ketone Ester and Subsequent Metabolites Us… (The AAPS journal 2025) · cited 1x in the literature
    "Here, the metabolic characteristics of one such supplement (Veech ketone mono-ester ((R)-3-hydroxybutyl(R)-3-hydroxybutyrate) (KE)) were studied along with its metabolite- (R)-1,3-butanediol ((R)-1,3-BD), both of which are precursors and undergo metabolic conversion to (R)-beta-hydroxybutyrate (BHB). The metabolism of aldol (an aldehyde intermediate between the conversion of (R)-1,3-BD to (R)-BHB was also evaluated" (abstract, results, passage verified)
    pubmedfull study (doi)
0:52:34Dominic D'Agostinosupportedmoderate

1,3-butanediol acetoacetate diester elevates blood levels of beta-hydroxybutyrate and acetoacetate in approximately a one-to-one ratio.

"The the 1,3-butanediol acetoacetate diester elevates beta-hydroxybutyrate and acetoacetate more or less in a one-to-one ratio." (said at 0:52:34)

Studies evaluating oral administration of 1,3-butanediol acetoacetate diester (BD-AcAc2) demonstrate that upon ingestion and cleavage into its constituent acetoacetate moieties and 1,3-butanediol (which is metabolized into beta-hydroxybutyrate), circulating concentrations of both acetoacetate (AcAc) and beta-hydroxybutyrate (BHB) increase rapidly in roughly equimolar (~1:1) proportions. For example, pharmacokinetic evaluation in animal models demonstrated concurrent elevations of both BHB and AcAc to >3 mM.

1:00:28Rhonda Patrick (host)supportedmoderate

Certain genetic polymorphisms cause some individuals to require two to three times the normal dose of vitamin D to raise blood levels to 30 to 40 ng/mL.

"there are polymorphisms that um some people uh require, you know, in some cases two to three times the normal dose to actually just bring you up to like a normal level of like 30 to 40 nanograms per mil." (said at 1:00:28)

The speaker's claim that genetic polymorphisms cause some individuals to require two to three times the normal dose of vitamin D to raise blood levels to normal levels (~30-40 ng/mL) is supported by clinical trials examining genetic variation in response to vitamin D supplementation. Key studies, such as Waterhouse et al. (2014) in *The Journal of Clinical Endocrinology & Metabolism*, showed that single-nucleotide polymorphisms (SNPs) in candidate genes—most prominently *CYP2R1* (which encodes the principal hepatic 25-hydroxylase enzyme)—significantly modulate individual 25-hydroxyvitamin D response to supplementation, noting that genetic variation means some individuals need higher doses to reach optimal circulating concentrations. Further studies (e.g., Nissen et al., 2017) examining variability in response found that carrying specific variants in *CYP2R1* or *RXRA* (such as rs11185644) substantially alters dose-response relationships, requiring non-responders or lower-responders to receive higher doses to achieve target blood levels.

1:02:06Rhonda Patrick (host)supportedhigh

Single nucleotide polymorphisms affect the enzymatic steps required to convert vitamin D3 into 25-hydroxyvitamin D.

"there's several that affect your ability to um convert. So there's There's several steps in vitamin D3 metabolism, but um to convert, yeah, vitamin D3, converting it into um to 25-hydroxyvitamin D, which is what is the major circulating form, which is what you're getting measured when you're getting a blood test. There's SNPs that affect that." (said at 1:02:06)

Large-scale genome-wide association studies (GWAS) and systematic reviews consistently demonstrate that single nucleotide polymorphisms (SNPs) in genes encoding vitamin D-metabolizing enzymes—most notably the hepatic 25-hydroxylase enzyme encoded by CYP2R1, as well as upstream synthesis genes such as DHCR7—significantly influence circulating 25-hydroxyvitamin D [25(OH)D] concentrations and conversion efficiency across diverse populations.

1:03:08Rhonda Patrick (host)supportedlow

Preliminary studies indicate that vitamin D2 supplementation may inhibit some of the biological actions of vitamin D in skeletal muscle.

"there was some There's some preliminary data, and I haven't checked back, I don't know how much of this has been confirmed, but vitamin D2 supplementation with vitamin D2 seemed to like inhibit some of the effects of vitamin D vitamin D in muscle, you know." (said at 1:03:08)

The speaker accurately characterizes this as preliminary data. In a double-blind randomized controlled trial of athletic subjects (NASCAR pit crew athletes), 6 weeks of daily vitamin D2 supplementation (3800 IU/day) significantly decreased circulating serum 25(OH)D3 levels (by 21%) and was associated with amplified post-exercise muscle damage biomarkers (such as myoglobin and creatine kinase) compared to placebo. Because the body of evidence is limited to small trials with surrogate markers of muscle damage, certainty is low.

1:03:36Rhonda Patrick (host)supportedhigh

Lichen species synthesize vitamin D3 and can be utilized as a vegan source of vitamin D3.

"a lot of vegetarians like to take vitamin D2 because, you know, they want something that's plant-based, but you can actually get vitamin D3 from lichen. Yeah, they produce vitamin D3." (said at 1:03:36)

Published chemical and nutritional analyses confirm that lichen species synthesize and accumulate vitamin D3 (cholecalciferol) upon exposure to ultraviolet light. Lichen extracts (such as from *Cladonia rangiferina* and epiphytic lichens) provide a commercially viable, plant-based (vegan) source of vitamin D3, offering an alternative to standard animal-derived vitamin D3 (lanolin) and fungal vitamin D2.

1:07:02Dominic D'Agostinosupportedvery low

Beta-hydroxybutyrate induces epigenetic modifications via histone deacetylase inhibition and histone beta-hydroxybutyrylation.

"beta-hydroxybutyrate has epigenetic effects as far as activating, you know, histone deacetylase inhibition, and also there's something called beta-hydroxybutyrylation, similar to lactylation. So beta-hydroxybutyrate can directly interact with the histone to cause epigenetic modifications" (said at 1:07:02)

Beta-hydroxybutyrate (BHB) acts as an epigenetic regulator through two well-documented biochemical mechanisms: acting as an endogenous inhibitor of Class I histone deacetylases (HDACs) and serving as the substrate donor for lysine β-hydroxybutyrylation (Kbhb) of histones. These modifications alter chromatin architecture and regulate transcription in response to fasting, ketogenic diets, and exogenous ketone elevation. Because evidence establishing these epigenetic pathways derives from in vitro and animal models, certainty under GRADE criteria is graded as very low.

1:07:28Dominic D'Agostinosupportedvery low

Research from Hans Bjornsson's laboratory at Johns Hopkins demonstrated that a ketogenic diet silenced neurological abnormalities in a mouse model of Kabuki syndrome.

"Kabuki syndrome, which is a rare genetic disease where the ketogenic diet, in the lab of Hans Bjornsson at Johns Hopkins, demonstrated that the ketogenic diet silenced these uh neurological abnormalities associated with this Kabuki syndrome, which is a rare genetic disorder and causes seizures, too." (said at 1:07:28)

A 2017 study from Hans Bjornsson's laboratory at Johns Hopkins University (Benjamin et al., PNAS) demonstrated that a ketogenic diet rescued adult neurogenesis deficiency in the dentate gyrus and reversed hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/βGeo mice) via elevation of beta-hydroxybutyrate acting as an endogenous histone deacetylase inhibitor. Because this evidence is derived from an animal model, the certainty is rated as very low.

1:08:20Dominic D'Agostinosupportedvery low

Acetoacetate stimulates skeletal muscle regeneration in muscular dystrophy through an ERK-MEK-cyclin D signaling pathway.

"Acetoacetate, on the other hand, has effects, at least in muscular dystrophy, in regards to increasing skeletal muscle regeneration, and it does it through an ERK-MEK-cyclin D, I think, uh mechanism." (said at 1:08:20)

Preclinical animal and in vitro research demonstrates that acetoacetate promotes muscle satellite cell proliferation, accelerates skeletal muscle regeneration in wild-type mice, and ameliorates pathology in mdx mouse models of muscular dystrophy via activation of the MEK1-ERK1/2-cyclin D1 signaling cascade. Because this evidence is currently limited to animal and cell models, certainty is very low regarding translation to human muscular dystrophy.

1:09:14Dominic D'Agostinosupportedmoderate

Intravenous infusion of beta-hydroxybutyrate in humans causes a sharp decrease in circulating alanine and preserves or elevates branched-chain amino acids such as leucine.

"when we administer, even in human studies if we IV-administer beta-hydroxybutyrate, there's a decrease, a sharp decrease, in alanine and also a preservation of branched-chain amino acids, like leucine is elevated, and it prevents a drop." (said at 1:09:14)

Human metabolic tracer studies demonstrate that intravenous infusion of sodium beta-hydroxybutyrate causes a significant decrease in circulating plasma alanine (falling by 25-35%) alongside an elevation or preservation of circulating branched-chain amino acids such as leucine.

1:13:24Dominic D'Agostinosupportedvery low

Lipopolysaccharide (LPS) administration causes extensive muscle wasting and sarcopenia over time in experimental models.

"We did a study with lipopolysaccharide, LPS. So LPS causes massive, you know, muscle wasting and sarcopenia with time. And in that model, too, the ketones are protective in some ways by inhibiting some of the anti-inflammatory inhibiting the inflammatory effects of LPS." (said at 1:13:24)

Preclinical and experimental animal models widely demonstrate that lipopolysaccharide (LPS) administration induces acute and systemic inflammation, leading to extensive skeletal muscle wasting and atrophy. LPS challenge triggers catabolic signaling pathways, including the upregulation of muscle-specific E3 ubiquitin ligases (such as Atrogin-1 and MuRF-1) and activation of inflammatory cascades (such as STAT3 and NF-κB), resulting in marked reductions in myofiber cross-sectional area and muscle mass. Because evidence for this specific disease model is derived from in vitro and animal models, the GRADE certainty is rated as very low.

1:19:34Dominic D'Agostinosupportedmoderate

Under hypoxic conditions, providing glucose supplements does not produce the ergogenic exercise performance improvements typically observed in normoxia.

"we know if we put athletes on a treadmill or bike in a hypoxic environment and give them glucose, that the performance-enhancing effects of glucose are not observed in hypoxia" (said at 1:19:34)

Evidence from randomized crossover trials and exercise metabolism reviews demonstrates that acute hypoxic exposure suppresses exogenous carbohydrate oxidation and peripheral glucose uptake during exercise. Unlike in normoxia, carbohydrate or glucose ingestion during endurance exercise under acute hypoxia generally fails to elicit meaningful ergogenic improvements in time-trial or endurance performance.

1:19:47Dominic D'Agostinosupportedhigh

Hypoxic conditions inhibit the activity of the pyruvate dehydrogenase enzyme complex during metabolic energy production.

"whereas it's also shown that there may be an inhibition under hypoxic environments of pyruvate dehydrogenase. So there might be some PDH deficiency or some snag or bottleneck in the metabolic pathway associated with glycolytic energy production under hypoxia." (said at 1:19:47)

The claim is supported by extensive biochemical and physiological literature. Under hypoxic conditions, hypoxia-inducible factor 1 (HIF-1) transactivates the gene encoding pyruvate dehydrogenase kinase 1 (PDK1) (and PDK4), which phosphorylates and inactivates the pyruvate dehydrogenase (PDH) complex. This inactivation prevents the conversion of pyruvate to acetyl-CoA, shunting glycolytic metabolites away from mitochondrial tricarboxylic acid (TCA) cycle oxidation towards lactate production and creating a bottleneck at the entry into oxidative metabolism.

1:21:14Dominic D'Agostinosupportedhigh

Carbohydrate restriction and low insulin levels inhibit glycolytic enzymes like hexokinase and promote internalization of glucose transporters.

"whenever we're doing carbohydrate restriction, we're limiting glucose availability, but also lowering insulin, and by lowering insulin especially, that inhibits glycolytic enzymes like hexokinase. It also like the the glucose there the transporter for glucose gets internalized into the cell if likely. So you don't, you know, the glycolytic flux is essentially decreased." (said at 1:21:14)

The speaker's statement accurately describes established physiological and biochemical mechanisms. In insulin-sensitive tissues (such as skeletal muscle and adipose tissue), insulin stimulates the translocation (exocytosis) of glucose transporters (principally GLUT4) to the cell surface and upregulates key glycolytic enzymes including hexokinase and phosphofructokinase. When dietary carbohydrate is restricted, circulating insulin levels drop, leading to the endocytosis (internalization) of surface GLUT4 back into intracellular compartments, reduced activity and expression of glycolytic enzymes, and a marked reduction in overall glycolytic flux.

1:21:44Dominic D'Agostinosupportedmoderate

Severe carbohydrate restriction decreases the expression and enzymatic activity of pyruvate dehydrogenase.

"I think I've seen data to indicate that severe carbohydrate restriction could decrease the production and the activity of PDH. This is actually what happens with Alzheimer's disease, too." (said at 1:21:44)

Human dietary intervention studies demonstrate that severe carbohydrate restriction (typically high-fat, low-carbohydrate diets with ~5% energy from carbohydrates) significantly decreases the enzymatic activity of active pyruvate dehydrogenase (PDHa) in skeletal muscle. Mechanistically, this occurs through the rapid upregulation of pyruvate dehydrogenase kinase (PDK, particularly the PDK4 isoform), which phosphorylates and inactivates PDH to conserve carbohydrate stores and shift substrate oxidation toward fat. While total PDH protein expression is largely preserved, its functional/active enzymatic activity is substantially reduced.

1:21:58Dominic D'Agostinosupportedhigh

Alzheimer's disease is characterized on FDG-PET scans by cerebral glucose hypometabolism.

"with Alzheimer's disease, it's pathophysiologically linked to impaired glucose metabolism. So if you do an FDG-PET scan, the PET scan shows glucose hypometabolism in the brain scan" (said at 1:21:58)

Cerebral glucose hypometabolism visualized by 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is an established hallmark and diagnostic biomarker of Alzheimer's disease (AD). Meta-analyses and neuroimaging studies consistently demonstrate characteristic regional patterns of reduced brain glucose metabolism (particularly in the posterior cingulate cortex, precuneus, and temporoparietal regions) in patients with AD compared to healthy controls.

1:08:52Dominic D'Agostinosupportedvery low

Ketone ester supplementation elevating both beta-hydroxybutyrate and acetoacetate prevents muscle wasting in experimental models of cachexia.

"So uh the the research that we've done uses an ester that elevates both of them and shown that it works in a model of cachexia." (said at 1:08:52)

Preclinical evidence supports the claim that ketone body elevation via ketogenic diet or exogenous ketone administration can attenuate cachexia and muscle wasting in cell line and animal models. For instance, treatment of pancreatic cancer cell lines and orthotopic mouse models with ketone bodies or a ketogenic diet demonstrated diminished tumor growth and reduced loss of muscle and body weight (PMID: 25228990). Similarly, acetoacetate and beta-hydroxybutyrate exhibit anticatabolic effects in skeletal muscle models (PMID: 30712977). However, results across experimental cancer models are variable; for example, exogenous ketone ester administration in a lung cancer mouse model failed to prevent muscle wasting or improve survival (PMID: 35719965). The evidence is restricted to experimental in vitro and animal models, corresponding to a very low certainty of evidence for general clinical application.

1:13:19Dominic D'Agostinosupportedmoderate

Cancer cachexia is characterized by marked elevation of inflammatory mediators including interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha).

"So with cachexia, for example, you have a high elevation of like IL-1 beta, TNF-alpha, which used to be called cachectin, I think, as inflammatory mediators." (said at 1:13:19)

Cancer cachexia is recognized as a systemic inflammatory syndrome driven by pro-inflammatory mediators. Published literature and clinical studies consistently identify tumor necrosis factor-alpha (TNF-alpha, historically termed cachectin) and interleukin-1 beta (IL-1 beta), alongside IL-6 and other cytokines, as significantly elevated mediators that promote skeletal muscle proteolysis, adipose tissue lipolysis, and anorexia.

1:15:36Dominic D'Agostinosupportedmoderate

Implementing a 5-day fasting-mimicking diet once per month provides long-lasting improvements in insulin sensitivity and metabolic biomarkers lasting weeks to over a month.

"fasting mimicking diet being implemented for just a 1-week or 5-day period, right, per month. And that can have long-lasting metabolic benefits even throughout, you know, weeks to even a month or more after you you do that as far as resetting insulin sensitivity and improving different metabolic biomarkers." (said at 1:15:36)

Randomized controlled trials evaluating 5-day cycles of a fasting-mimicking diet (FMD) administered once per month demonstrate improvements in metabolic biomarkers and insulin sensitivity that persist beyond the fasting days. In clinical trials of healthy adults and individuals with metabolic risk factors, 3 monthly cycles of a 5-day FMD reduced insulin resistance (HOMA-IR), hepatic fat, fasting glucose, and other cardiometabolic risk markers measured during normal refeeding periods. Furthermore, a randomized trial in patients with type 2 diabetes undergoing 6 monthly cycles found that reductions in HOMA-IR were sustained at a 3-month follow-up post-intervention.

1:12:12Rhonda Patrick (host)supportedmoderate

Consuming refined carbohydrates prior to exercise blunts endurance-induced mitochondrial adaptations compared to exercising in a fasted state.

"I've been reading some meta-analyses over the years about training in an uh fasted state versus fed state and how, you know, if you eat before, you know, you go for a run or something, that, you know, a lot of the mitochondrial adaptations can be blunted somewhat. And, of course, a lot of those studies are using high refined carbohydrate" (said at 1:12:12)

A systematic review and meta-analysis examining fasted versus fed-state exercise (Aird et al., 2018) confirmed that pre-exercise feeding (frequently utilizing high-glycemic or refined carbohydrate meals/solutions in the included trials) blunted key skeletal muscle and adipose tissue signaling pathways involved in mitochondrial adaptations and fat oxidation compared to fasted exercise. While pre-exercise carbohydrate feeding enhances prolonged endurance performance, exercising in the fasted state produces higher acute activation of upstream transcriptional regulators (such as AMPK and fat oxidative gene expression) related to mitochondrial biogenesis.

1:31:20Rhonda Patrick (host)supportedvery low

Preclinical studies by Dr. Eric Verdin and Dr. John Ramsey showed that feeding mice a cyclical ketogenic diet in midlife improved median lifespan and healthspan without affecting maximum lifespan.

"preclinical studies that have come out of our mutual friend Dr. Eric Verdin, and I know John Ramsey also did some publications where they fed mice in the case of Dr. Verdin's study mid- midlife, they started him on a cyclical cyclical ketogenic diet... their healthspan was improved. Um their median So their median lifespan was improved, so they were dying they were dying less earlier, but maximum lifespan, I guess, wasn't affected." (said at 1:31:20)

Preclinical studies published in 2017 by Dr. Eric Verdin's group (Newman et al.) and Dr. John Ramsey's group (Roberts et al.) investigated the effects of ketogenic diets initiated in adult/midlife mice (12-14 months of age). Verdin's group tested a cyclical ketogenic diet (alternated weekly with a control diet to avoid obesity) and found that it significantly reduced midlife mortality and improved healthspan and memory, while maximum lifespan remained unaffected. Ramsey's group similarly demonstrated that an isocaloric ketogenic diet increased median lifespan and preserved physiological function/healthspan in aging mice. Because this evidence is derived exclusively from rodent models, the GRADE certainty is very low regarding translation to humans.

1:35:10Dominic D'Agostinosupportedvery low

Rodent studies by Verdin and Ramsey demonstrated suppression of spontaneous tumor formation on a ketogenic diet.

"And I think in their studies, maybe with both or at least one, maybe both studies showed a suppression of spontaneous tumors, too." (said at 1:35:10)

Two companion 2017 rodent longevity studies from the laboratories of Jon Ramsey (Roberts et al., 2017) and Eric Verdin (Newman et al., 2017) investigated the effects of ketogenic diets initiated in middle-aged mice on lifespan and healthspan. Roberts et al. observed that mice on a continuous ketogenic diet had a lower incidence of spontaneous tumors and increased median lifespan compared to control-fed mice. Because the supporting evidence comes strictly from preclinical rodent models, the certainty of evidence for human health outcomes is rated very low.

1:36:00Dominic D'Agostinosupportedvery low

Mark Mattson's research showed that benefits of intermittent fasting are associated with beta-hydroxybutyrate-induced increases in brain-derived neurotrophic factor (BDNF).

"Mattson's work actually showed that many of the benefits of intermittent fasting were associated with beta-hydroxybutyrate-induced growth factor effects on like BDNF and things like that." (said at 1:36:00)

Research from Mark P. Mattson's laboratory demonstrated that the ketone body beta-hydroxybutyrate (3-hydroxybutyrate, 3OHB)—which rises during fasting and vigorous exercise—stimulates brain-derived neurotrophic factor (BDNF) expression in cultured cortical neurons via mitochondrial respiration, reactive oxygen species generation, NF-κB activation, and histone acetyltransferase activity. Because this mechanistic evidence derives from in vitro and animal models, certainty regarding translational clinical outcomes in humans remains very low.

  • supports: 3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cort… (Journal of neurochemistry 2016) · cited 242x in the literature
    "We found that 3OHB metabolism increases mitochondrial respiration which drives changes in expression of brain-derived neurotrophic factor (BDNF) in cultured cerebral cortical neurons. The mechanism by which 3OHB induces Bdnf gene expression involves generation of reactive oxygen species, activation of the transcription factor NF-κB, and activity of the histone acetyltransferase p300/EP300. Because BDNF plays important roles in synaptic plasticity and neuronal stress resistance, our findings suggest cellular signaling mechanisms by which 3OHB may mediate adaptive responses of neurons to fasting, exercise, and ketogenic diets." (abstract, results, passage verified)
    pubmedfull study (doi)
1:39:30Dominic D'Agostinosupportedvery low

A clinical case report documented that Dr. Mary Newport's husband experienced cognitive improvements and symptom reversal in Alzheimer's disease using a beta-hydroxybutyrate ketone ester.

"there was a case report written on the use of beta-hydroxybutyrate ester as a therapy, and this case report was her husband. And I witnessed that her husband—she had many more years, uh, well, you know, years, maybe like five or six years, just from an outsider looking in, it seemed like she had that amount of time extra with her husband to spend because of the ketogenic intervention." (said at 1:39:30)

A published case report authored by Dr. Mary T. Newport and colleagues documented the use of a ketone monoester (a beta-hydroxybutyrate ester) in a patient with Alzheimer's disease (her husband, Steve Newport). The publication reported marked improvements in mood, affect, self-care, cognitive performance, and daily activity tracking plasma beta-hydroxybutyrate concentrations over a 20-month treatment period. Because this evidence is limited to a single case report, the certainty of evidence for general clinical efficacy in Alzheimer's disease is very low.

1:41:35Dominic D'Agostinosupportedmoderate

In Accera's clinical trial of AC-1202 (tricaprylin/MCT), ApoE4-positive Alzheimer's disease patients were non-responsive to hyperketonemia compared to ApoE4-negative patients.

"So there was no doubt in the study of Accera in AC-1202, the ApoE4 phenotypes were the ones that were not responsive to hyperketonemia, but he's ApoE4 and he was responsive" (said at 1:41:35)

In the randomized, double-blind, placebo-controlled trial evaluating the ketogenic compound AC-1202 (tricaprylin) sponsored by Accera in 152 patients with mild to moderate Alzheimer's disease (Henderson et al., 2009), cognitive benefits were stratified by APOE4 carriage status. While AC-1202 induced hyperketonemia (elevating serum beta-hydroxybutyrate), significant improvements in ADAS-Cog cognitive scores compared to placebo were observed almost entirely in APOE4-negative patients (e.g., a 4.77 to 6.26-point improvement depending on the analysis cohort), with a significant correlation between beta-hydroxybutyrate levels and cognitive response only in the APOE4-negative group. APOE4-positive patients did not exhibit a significant cognitive response to AC-1202-induced hyperketonemia.

  • supports: Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized… (Nutrition & metabolism 2009) · cited 546x in the literature
    "Among participants who did not carry the APOE4 allele (E4(-)), a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45 and Day 90. In the ITT population, E4(-) participants (N = 55) administered AC-1202 had a significant 4.77 point difference in mean change from Baseline in ADAS-Cog scores at Day 45 (p = 0.0005) and a 3.36 point difference at Day 90 (p = 0.0148) compared to Placebo... Furthermore, a significant pharmacologic response was observed between serum beta-hydroxybutyrate levels and change in ADAS-Cog scores in E4(-) subjects at Day 90 (p = 0.008)." (abstract, results, passage verified)
    pubmedfull study (doi)
1:56:46Dominic D'Agostinosupportedmoderate

Dr. Elena Gross and Dr. Dominic D'Agostino published a review documenting that ketogenic diets and exogenous ketone supplements can help manage chronic migraines.

"In regards to migraines, a PhD student by the name of—or now Dr. Elena Gross, so we wrote a review together which kind of highlighted many of the benefits associated with migraines. So she was a person who had crushing migraines and discovered that the ketogenic diet and then later ketone supplements could recapitulate that and actually help to manage her chronic migraines that she had." (said at 1:56:46)

Dr. Elena Gross and Dr. Dominic D'Agostino co-authored a published narrative review in 2019 ('Potential Protective Mechanisms of Ketone Bodies in Migraine Prevention') examining how nutritional ketosis induced by the ketogenic diet or exogenous ketone bodies (specifically D-beta-hydroxybutyrate) acts on metabolic, mitochondrial, oxidative stress, and neuroinflammatory pathways involved in migraine pathophysiology.

2:03:00Dominic D'Agostinosupportedvery low

Research by Dr. Adrienne Scheck showed that combining a dietary intervention with radiation enhanced cancer-specific immune regulation in a glioblastoma cell line.

"So a colleague of mine, Dr. Adrienne Scheck, did research with a glioblastoma cell line showing enhanced cancer-specific immune regulation with a dietary intervention. She was also using radiation." (said at 2:03:00)

Preclinical research led by Dr. Adrienne C. Scheck demonstrated that a ketogenic diet acts as an adjuvant therapy in glioma models. Her group showed that a ketogenic diet significantly enhanced the anti-tumor efficacy of radiation therapy in an intracranial mouse glioma model (GL261-Luc2), and separately established that the dietary intervention enhanced tumor-reactive innate and adaptive immune responses (including increased CD8+ T-cell cytolysis and reduced CTLA-4/PD-1 inhibitory receptor expression). Because this evidence is derived from preclinical mouse glioma models, certainty regarding translation to human glioblastoma remains very low.

2:05:33Dominic D'Agostinosupportedvery low

Published research demonstrates that PD-L1 immune checkpoint inhibitors are greatly augmented in efficacy when combined with a ketogenic diet.

"There's a big—a paper just came out in a pretty high-impact journal, I forget the name of the journal, but it showed that PD-L1 inhibitors were greatly augmented in the context of the ketogenic diet." (said at 2:05:33)

Preclinical studies published in high-impact journals demonstrate that a ketogenic diet or its primary ketone body, beta-hydroxybutyrate (3HB), enhances the efficacy of immune checkpoint blockade (including PD-1/PD-L1 and CTLA-4 inhibitors) in syngeneic mouse tumor models. However, this evidence is strictly preclinical (rodent and cell models), and clinical efficacy in human cancer patients undergoing immunotherapy remains under investigation in early-phase clinical trials.

2:11:40Dominic D'Agostinosupportedvery low

Adding exogenous ketones to a standard diet extended survival in animal models with metastatic cancer beyond what was achieved by 25% calorie restriction alone.

"We know this because if we put exogenous ketones into a standard diet, we can extend the life of animals that have metastatic cancer. So we've published that in the International Journal of Cancer. But what was happening was, when you put the ketones in the standard diet food, they probably eat a little bit less, and it's also lowering blood glucose and changing metabolic physiology. But so it may not be—and then the reviewers rightly asked, they said, "Well, go do a calorie restriction group." So we took a standard diet and calorie restricted like 25%, and we saw an increase in survival, but it was nowhere near the increase in survival from adding the ketones to the standard diet." (said at 2:11:40)

In a 2014 study published in the International Journal of Cancer by Poff et al., dietary ketone supplementation (with 1,3-butanediol or a ketone ester added to a standard diet) significantly prolonged survival in VM mice bearing metastatic VM-M3 cancer cells (by 51% and 69%, respectively). The authors evaluated the effect alongside calorie restriction and demonstrated that exogenous ketones extended survival independently of and beyond calorie restriction alone. Because the evidence is limited to pre-clinical mouse models, the overall certainty for clinical translation is very low.

1:59:45Dominic D'Agostinosupportedlow

Certain omega-3 fatty acids increase carnitine palmitoyltransferase activity and augment fat oxidation.

"whereas we know that certain omega-3 fatty acids can actually increase the carnitine, you know, transferase and actually augment fat oxidation—certain fatty acids can." (said at 1:59:45)

Preclinical in vitro and animal studies support the claim that specific omega-3 polyunsaturated fatty acids (such as DHA, EPA, and ALA from perilla or fish oils) can upregulate carnitine palmitoyltransferase-1 (CPT1) expression and activity and enhance fatty acid oxidation. For instance, in skeletal muscle cell models, DHA treatment has been shown to significantly elevate palmitate oxidation and increase protein levels of CPT1b and PGC-1α. Because evidence for this specific cellular enzymatic mechanism is primarily derived from in vitro and animal models, certainty is graded as low.

2:01:58Dominic D'Agostinosupportedmoderate

Butyrate is the primary metabolic fuel source for colonocytes.

"It is, yeah, and it's a primary fuel for colonocytes." (said at 2:01:58)

Published physiological and biochemical studies establish that the short-chain fatty acid butyrate, produced by anaerobic bacterial fermentation of dietary fiber in the large intestine, serves as the primary respiratory and energy fuel for colonic epithelial cells (colonocytes). Classic respirometry in isolated human colonocytes demonstrated that butyrate oxidation accounts for up to 70% or more of total oxygen consumption in these cells, exceeding the energy contribution of circulating glucose or glutamine.

2:09:55Dominic D'Agostinosupportedhigh

The carbon atoms exhaled as breath acetone originate from the breakdown of fatty acids.

"So all the carbons of the acetone you're blowing off essentially are from fat. So when you look at the device and it's reading like 40, it's like you're basically exhaling fat carbons from that." (said at 2:09:55)

Biochemically, breath acetone is a volatile byproduct of hepatic ketogenesis. During periods of fasting, carbohydrate restriction, or caloric deficit, increased lipolysis and hepatic beta-oxidation break down fatty acids into acetyl-CoA. Acetyl-CoA units condense to form acetoacetate, which subsequently undergoes spontaneous or enzymatic decarboxylation to form acetone (a 3-carbon molecule). This acetone diffuses into the alveolar air and is exhaled, meaning its carbon skeleton is derived from fatty acid metabolism (with negligible contributions from ketogenic amino acids under typical conditions).

2:13:23Rhonda Patrick (host)supportedvery low

Published rodent studies by Eric Verdin and John Ramsey showed a reduction in the incidence of spontaneous tumors on a ketogenic diet.

"as you mentioned earlier with Dr. Eric Verdin and John Ramsey's co-published studies, there was a reduction, and there's a possible preventative mechanism as well, with at least according to animal research, there being a reduction in spontaneous tumors in these rodents." (said at 2:13:23)

Two companion studies published simultaneously in Cell Metabolism by John Ramsey's group (Roberts et al., 2017) and Eric Verdin's group (Newman et al., 2017) evaluated the effects of ketogenic diets on longevity and healthspan in aging C57BL/6 mice. Roberts et al. (senior author John Ramsey) specifically reported that a continuous ketogenic diet significantly extended median lifespan, improved physical performance in aged mice, and lowered spontaneous tumor incidence at necropsy compared with control diets. Newman et al. (senior author Eric Verdin) demonstrated that a cyclic ketogenic diet significantly reduced midlife mortality and preserved memory function. Because these findings are derived entirely from non-human animal models, the clinical evidence certainty for humans remains very low.

2:19:15Dominic D'Agostinosupportedmoderate

Primary or secondary carnitine deficiency manifests clinically with elevated triglycerides and hypoketonemia due to impaired fatty acid metabolism.

"if you have an inborn error of metabolism like carnitine deficiency, either primary or secondary, a telltale sign is like an elevation of triglycerides, hypoketonemia, and then you have like, you know, a cascade of different things. Like you're just not metabolizing fat as well as you should be" (said at 2:19:15)

Primary carnitine deficiency (caused by mutations in the SLC22A5 gene encoding the OCTN2 carnitine transporter) and secondary carnitine deficiencies disrupt mitochondrial fatty acid transport and beta-oxidation. Because ketone bodies are produced from acetyl-CoA generated through mitochondrial beta-oxidation of fatty acids, defective fatty acid oxidation characteristically presents with hypoketotic hypoglycemia (hypoketonemia alongside low glucose during fasting or metabolic stress), hepatic steatosis, and impaired fat utilization.

  • supports: Functional and molecular studies in primary carnitine deficiency. (Human mutation 2017) · cited 79x in the literature
    "Primary carnitine deficiency is caused by a defect in the OCTN2 carnitine transporter encoded by the SLC22A5 gene. It can cause hypoketotic hypoglycemia or cardiomyopathy in children, and sudden death in children and adults." (abstract, results, passage verified)
    pubmedfull study (doi)
  • supports: Fatty acid oxidation disorders. (Annals of translational medicine 2018) · cited 204x in the literature
    "Fatty acid oxidation disorders (FAODs) are inborn errors of metabolism due to disruption of either mitochondrial β-oxidation or the fatty acid transport using the carnitine transport pathway. The presentation of a FAOD will depend upon the specific disorder, but common elements may be seen, and ultimately require a similar treatment. Initial presentations of the FAODs in the neonatal period with severe symptoms include cardiomyopathy, while during infancy and childhood liver dysfunction and hypoketotic hypoglycemia are common." (abstract, results, passage verified)
    pubmedfull study (doi)
2:31:29Dominic D'Agostinosupportedvery low

Acetone has anticonvulsant properties and contributes to seizure control.

"seizure control, acetone does." (said at 2:31:29)

Preclinical animal models and pharmacological reviews confirm that acetone, a ketone body produced during fasting and the ketogenic diet, has direct, broad-spectrum anticonvulsant actions. In rodent models (including pentylenetetrazol-, maximal electroshock-, and 4-aminopyridine-induced seizure assays), acetone dose-dependently raises seizure thresholds and protects against convulsive activity. However, evidence for its direct anticonvulsant role comes primarily from animal and mechanistic research, as direct clinical trials of acetone administration in humans are lacking.

2:31:35Dominic D'Agostinosupportedmoderate

Urine ketone strips are not very accurate and provide only semi-quantitative measurement of ketosis.

"the urine ketone strips are not very accurate. So to answer your question, I think both blood ketone measurements—if you're just starting the ketogenic diet, it may be good to just use urine to say, yes, you're in ketosis, you're not, it's like semi-quantitative" (said at 2:31:35)

Clinical evidence supports the claim that urine ketone test strips are imprecise and provide only semi-quantitative assessment of ketosis. Urine dipsticks measure urinary acetoacetate using color blocks (e.g., negative, trace, weak, medium) rather than exact numerical concentrations. A clinical evaluation comparing urine dipsticks against blood beta-hydroxybutyrate measurements in individuals undergoing dietary energy restriction found that urine dipsticks had poor diagnostic accuracy and low sensitivity for detecting mild nutritional ketosis (missing up to 48% to 65% of true ketosis instances at typical nutritional thresholds of 0.3–0.5 mM blood beta-hydroxybutyrate).

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.