DavidPerlmutterMD · 2021-10-04 · David Perlmutter (host), Steven Gundry

What Our Fatigue Reveals About Our Health - with Dr. Gundry | The Empowering Neurologist EP. 134

37 research-tied claims examined: 2 contradicted 1 overstated 2 context 24 supported 8 unverified

24

Supported by research

0:14:15Steven Gundrysupportedmoderate

A Duke University study found that the daily energy expenditure of Hadza hunter-gatherers was virtually identical to that of sedentary desk workers.

"early on in the book I bring up the study that was done by Duke University researchers a few years ago looking at the Hadzas, one of the last hunter-gatherer tribes in Tanzania, and comparing their energy expenditure to desk workers, sedentary desk workers... lo and behold, the energy expenditure of the office workers was virtually identical to the Hadzas." (said at 0:14:15)

A 2012 study led by Herman Pontzer and colleagues measured total daily energy expenditure (using the gold-standard doubly labeled water method) in Hadza hunter-gatherers in Tanzania and compared them to Western populations. Despite having significantly higher physical activity levels, the Hadza foragers had daily energy expenditures that were not significantly different from Westerners after controlling for body size and fat-free mass.

  • supports: Hunter-gatherer energetics and human obesity. (PloS one 2012) · cited 362x in the literature
    "In this study, we used the doubly-labeled water method to measure total daily energy expenditure (kCal/day) in Hadza hunter-gatherers to test whether foragers expend more energy each day than their Western counterparts. As expected, physical activity level, PAL, was greater among Hadza foragers than among Westerners. Nonetheless, average daily energy expenditure of traditional Hadza foragers was no different than that of Westerners after controlling for body size." (abstract, results, passage verified)
    pubmedfull study (doi)
0:22:15Steven Gundrysupportedhigh

Dietary fat is absorbed through the lymphatic system rather than directly into the bloodstream.

"fat, as most of us know, takes a very circuitous route to reach our mitochondria. It actually is absorbed through our lymphatic system rather than directly into our bloodstream." (said at 0:22:15)

Dietary long-chain triglycerides are packaged by intestinal enterocytes into chylomicrons, which enter specialized lymphatic capillaries in the intestinal villi (lacteals) rather than absorbing directly into the portal venous bloodstream. The lymphatic vessels then transport these lipids through the thoracic duct into the systemic venous circulation.

0:27:14Steven Gundrysupportedhigh

Mitochondria have their own DNA that is inherited exclusively from the mother.

"mitochondria have their own DNA, and we inherit our mitochondrial DNA from our mother. Dads contribute nothing" (said at 0:27:14)

Human mitochondria possess their own distinct genome (mtDNA), which is strictly inherited through the maternal lineage. While rare reports previously proposed potential paternal transmission, comprehensive whole-genome analyses have demonstrated that these cases reflect nuclear-encoded mitochondrial DNA insertions (mega-NUMTs) transmitted via paternal chromosomes rather than true paternal mitochondrial DNA transmission. Under normal human reproductive biology, paternal mtDNA is actively degraded or eliminated upon fertilization, resulting in exclusively maternal inheritance of mitochondrial DNA.

0:28:45Steven Gundrysupportedhigh

The discovery of nitric oxide's biological signaling mechanisms won the Nobel Prize for Physiology or Medicine.

"one of those discoveries won the Nobel Prize for Medicine in terms of how nitric oxide works." (said at 0:28:45)

The 1998 Nobel Prize in Physiology or Medicine was awarded jointly to Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad for their discoveries demonstrating that nitric oxide functions as a biological signaling molecule, particularly in the cardiovascular system.

0:28:50Steven Gundrysupportedhigh

The gut microbiome converts prebiotic fiber into postbiotics, including short-chain fatty acids like acetate, butyrate, and propionate, and gasotransmitters.

"The microbiome, when they are given prebiotic fiber, which is what they like to eat, they turn that prebiotic fiber into what are now called postbiotics. And postbiotics, in general, are two forms: one are short-chain fatty acids like acetate, butyrate, and propionate, and gasotransmitters, gaso-messengers." (said at 0:28:50)

Extensive literature confirms that the gut microbiome ferments prebiotic dietary fibers into bioactive microbial metabolites (frequently referred to as postbiotics or postbiotic metabolites), predominantly short-chain fatty acids (SCFAs)—specifically acetate, propionate, and butyrate—alongside microbial gases and signaling molecules (gasotransmitters). While formal consensus definitions (such as that from ISAPP) technically define postbiotics as inanimate microbial cells and/or their components with a health benefit, metabolic end-products like SCFAs generated from prebiotic fermentation are widely recognized as key functional mediators of microbiome-host interactions.

0:16:50David Perlmutter (host)supportedmoderate

Chronic immune activation results in a deficiency of intracellular NAD within immune cells.

"and we know that in the chronic immune state, there is a deficiency of NAD, intracellular NAD, within immune cells, and hence the push to restore intracellular NAD." (said at 0:16:50)

Preclinical and mechanistic evidence demonstrates that chronic inflammatory and immune-activated states lead to intracellular NAD+ depletion within immune cells (such as macrophages and T cells). Inflammatory stimuli and senescence-associated cytokines upregulate key NAD-consuming ectoenzymes—predominantly CD38—and disrupt cytosolic NAD-recycling shuttles, causing significant intracellular NAD+ degradation and metabolic dysfunction in immune cells.

0:29:47Steven Gundrysupportedhigh

Hydrogen gas is the smallest molecule in existence and is instantly diffusible through the gut wall.

"particularly hydrogen gas, is the smallest molecule there is and is instantly diffusible through the wall of our gut." (said at 0:29:47)

Molecular hydrogen (H2) has a molecular weight of approximately 2 Da, making it the lightest and smallest known molecule. Due to its minimal molecular size, neutral charge, and non-polar nature, hydrogen gas diffuses rapidly across biological membranes, including the cellular barriers of the gastrointestinal tract, into tissues and systemic circulation.

0:32:50David Perlmutter (host)supportedlow

Uric acid inhibits the activity of endothelial nitric oxide synthase (eNOS).

"And we know that uric acid inhibits the way that nitric oxide, at least endothelial eNOS, is able to do its job." (said at 0:32:50)

In vitro and animal models show that elevated uric acid impairs endothelial nitric oxide synthase (eNOS) activity and reduces nitric oxide (NO) production through mechanisms including PKC-dependent inhibitory eNOS phosphorylation (at Thr495), down-regulation of eNOS expression, and inhibition of the Akt/eNOS pathway.

0:36:26David Perlmutter (host)supportedhigh

Humans carry a mutation in the uricase gene that prevents the breakdown of uric acid.

"So we have a gene mutation in the uricase gene so that we cannot break down uric acid. It lingers." (said at 0:36:26)

Humans and other hominoids carry inactivating loss-of-function nonsense/frameshift mutations in the urate oxidase (uricase) gene (*UOX*). In most other mammals, functional uricase oxidizes uric acid into allantoin. Because humans lack functional uricase, they cannot break down uric acid via this enzyme, leading to higher circulating uric acid levels than in most non-hominoid mammals.

0:38:40Steven Gundrysupportedhigh

In individuals without insulin resistance, liver ketone production begins after approximately 12 hours of fasting.

"First of all, we begin producing, if we don't have insulin resistance, after about 12 hours of not eating, we begin to start producing ketones in our liver." (said at 0:38:40)

The claim is supported by established human physiology literature. As liver glycogen stores become depleted during fasting—typically beginning around 12 to 14 hours after food intake in healthy individuals with normal insulin sensitivity—circulating insulin levels drop and the liver initiates fatty acid oxidation and the synthesis of ketone bodies (primarily acetoacetate and beta-hydroxybutyrate).

0:39:15Steven Gundrysupportedmoderate

Ketones act as signaling molecules that prompt mitochondria to repair themselves and undergo mitogenesis.

"ketones are actually a miracle signaling molecule for mitochondria to do two things: to signal them to actively undergo repair work and to actively duplicate themselves, mitogenesis, make more of themselves." (said at 0:39:15)

Ketone bodies, particularly β-hydroxybutyrate (β-HB), function not only as metabolic fuels but also as signaling molecules (e.g., via cell surface receptors and endogenous histone deacetylase inhibition). Published mechanistic reviews and experimental studies document that β-HB signaling regulates mitochondrial quality control, including stimulating mitophagy and repair pathways, as well as promoting mitochondrial biogenesis.

0:40:45Steven Gundrysupportedhigh

Elevated insulin prevents ketosis by suppressing hormone-sensitive lipase, blocking the release of free fatty acids from adipocytes.

"But so when insulin is elevated, as I talk about in the book, you can't get into ketosis. I'm sorry, folks, it's impossible, because insulin suppresses hormone-sensitive lipase, which allows free fatty acids to be released from fat cells, and insulin stops that." (said at 0:40:45)

The biochemical mechanism described by the speaker is well established. Insulin is the primary anti-lipolytic hormone in humans. When circulating insulin levels are elevated, insulin signaling suppresses key intracellular lipolytic enzymes in adipocytes, including hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL). This inhibition prevents the breakdown of stored triglycerides and stops the release of non-esterified free fatty acids (NEFAs) into the bloodstream. Because hepatic ketogenesis requires a substantial flux of free fatty acids to the liver as substrate, insulin suppression of lipolysis effectively prevents or halts ketosis.

0:42:05Steven Gundrysupportedmoderate

The gut microbiome of the Hadza hunter-gatherers undergoes cyclical, seasonal shifts in composition.

"I think one of the things that's fascinating about them, and I write about this in the book, is their microbiome changes seasonally. Yes, and dramatic shifts in a circadian rhythm seasonally" (said at 0:42:05)

A longitudinal study analyzing 350 stool samples collected across more than a year from the Hadza hunter-gatherers of Tanzania demonstrated annual, cyclic reconfiguration of the gut microbiome. The researchers found that specific bacterial taxa drop to undetectable levels in one season (dry vs. wet) and reappear in the subsequent season, reflecting seasonal shifts in diet and lifestyle.

0:48:40Steven Gundrysupportedlow

Microglial activation triggered by gut permeability and inflammatory cytokines leads to synaptic and dendritic degradation in the brain.

"And the the evidence now that microglial activation by leaky gut, by inflammatory cytokines, unleashes just this torrent of neuroinflammation, which among other things, as you know, literally eats away on the dendritic processes in an effort to protect the neuron that they're, you know, designed to defend." (said at 0:48:40)

Preclinical studies and reviews support the mechanism described: systemic inflammatory signals and gut-derived bacterial products (such as lipopolysaccharide entering circulation and crossing the blood-brain barrier) activate microglia and induce neuroinflammation. When pathologically activated, microglia shift from physiological synaptic remodeling to excessive engulfment and degradation of synapses and dendritic spines (primarily via complement pathways like C1q-C3). However, direct causal evidence linking clinical gut permeability to microglial dendritic elimination in living humans remains largely derived from animal models, in vitro experiments, and indirect human biomarker associations, which limits the certainty.

0:52:10David Perlmutter (host)supportedmoderate

Radionuclide-labeled glucose imaging can detect regional brain glucose hypometabolism and predict Alzheimer's disease 10 years in advance.

"We know that we can predict now by using radionuclide-labeled glucose what parts of the brain are having deficiencies of glucose utilization. We can predict Alzheimer's a decade ahead of time." (said at 0:52:10)

Radionuclide-labeled glucose imaging (specifically [18F]-fluorodeoxyglucose positron emission tomography, or 18F-FDG PET) directly visualizes regional cerebral glucose utilization and detects patterns of hypometabolism characteristic of Alzheimer's disease pathology. Longitudinal cohort data, including analyses from the Alzheimer's Disease Neuroimaging Initiative (ADNI), demonstrate that baseline regional glucose hypometabolism on FDG-PET accurately predicts long-term cognitive decline and conversion to Alzheimer's disease over 10-year follow-up intervals in cognitively normal and at-risk older adults.

0:57:45Steven Gundrysupportedvery low

Melatonin is synthesized directly inside human mitochondria.

"But melatonin is actually the major mitochondrial antioxidant, and it's so important that our mitochondria actually make melatonin." (said at 0:57:45)

Biochemical and cellular studies confirm that melatonin is synthesized within mitochondria, including in human and mammalian tissues, where it functions as a locally produced antioxidant and signaling molecule. Research demonstrates that the enzymes required for melatonin biosynthesis (such as AANAT) are present within the mitochondrial matrix.

0:59:05David Perlmutter (host)supportedlow

Sleeping six hours or less per night is associated with an approximately 30% increased risk of diagnosed dementia.

"Well, there's a big report this week looking at increased risk of dementia, not just cognitive decline, but actually diagnosed dementia with under seven hours, around six hours or less of sleep, increased risk by about 30%." (said at 0:59:05)

A 2021 prospective cohort analysis of 7,959 participants from the Whitehall II study with 25 years of follow-up found that short sleep duration (six hours or less per night) in midlife (ages 50 and 60) and persistent short sleep duration across midlife and older age (ages 50, 60, and 70) were associated with an approximately 30% increased risk of incident diagnosed dementia compared to a normal sleep duration of seven hours, independent of sociodemographic, cardiometabolic, and mental health covariates. Because the evidence comes from an observational cohort, certainty is rated as low.

0:36:26David Perlmutter (host)supportedvery low

Uric acid directs energy metabolism away from AMP-activated protein kinase (AMPK) and into AMP deaminase, promoting lipogenesis.

"It feeds back to continue the metabolism of this fructose down a pathway away from AMP kinase into AMP deaminase, which tells the body, "Make fat. Winter's coming."" (said at 0:36:26)

The speaker accurately describes a molecular mechanism demonstrated in preclinical cell culture and animal models. During fructose metabolism, ATP depletion and intracellular phosphate reduction activate AMP deaminase (AMPD2), which converts AMP to uric acid. Research shows that uric acid inhibits AMP-activated protein kinase (AMPK) activity in human hepatocytes and rat livers, shifting AMP flux toward AMPD, inducing mitochondrial oxidative stress, and driving de novo lipogenesis (fat accumulation). However, because this evidence comes entirely from in vitro hepatocyte experiments and rodent models, the certainty for human physiological applicability remains very low.

0:42:39David Perlmutter (host)supportedlow

The gut microbiome of bears shifts significantly between the summer feeding period and winter hibernation.

"Well, there's one study it was quite interesting looking at the changes in the microbiome of the bear during feast and during hibernation, and how dramatically different they are." (said at 0:42:39)

A 2016 study published in Cell Reports investigated the fecal microbiota of wild brown bears (Ursus arctos) during the active summer feeding period and winter hibernation. The researchers found marked seasonal shifts: during hibernation, the gut microbiota exhibited significantly reduced bacterial diversity, decreased relative abundance of Firmicutes and Actinobacteria, and increased Bacteroidetes compared to the summer active phase.

0:54:00Steven Gundrysupportedmoderate

The glymphatic system clears metabolic waste and interstitial fluid from the brain primarily during deep sleep.

"During sleep, there is a brainwash cycle that you're well aware of, that I know your listeners are well aware of, where the glymphatic system, if you will, the lymphatic system of the brain, does a brainwash. And there is a need for increased blood flow to accomplish this brainwash. Normally this occurs during deep sleep" (said at 0:54:00)

Preclinical and translational human studies demonstrate that the glymphatic system facilitates the exchange of cerebrospinal fluid (CSF) with interstitial fluid (ISF) to clear metabolic waste products (such as amyloid-beta and tau) from the brain primarily during sleep, with peak clearance occurring during non-rapid eye movement (NREM) slow-wave (deep) sleep. Rodent experiments demonstrate that natural sleep expands the interstitial space by approximately 60%, accelerating waste removal, while human neuroimaging and biomarker studies confirm that slow-wave sleep and slow-wave oscillatory dynamics correlate with enhanced cerebral waste clearance.

1:01:12Steven Gundrysupportedhigh

Asparagus and artichokes are rich sources of inulin.

"Asparagus, which is in season right now, another great source of inulin. Artichokes and artichoke hearts, another great source of inulin." (said at 1:01:12)

Asparagus and artichokes (both globe artichokes and Jerusalem artichokes) are well-established dietary sources of inulin and related prebiotic fructans. Published compositional analyses and reviews consistently identify members of the Asteraceae family (including artichokes) and asparagus as prominent natural sources of inulin.

1:01:43Steven Gundrysupportedhigh

Purple sweet potatoes contain anthocyanins, which are polyphenols.

"And it also has anthocyanins, which are this phenomenal polyphenol." (said at 1:01:43)

The claim is accurate. Purple sweet potatoes (Ipomoea batatas) are rich in anthocyanins, which are a class of water-soluble polyphenols (flavonoids) responsible for their deep purple pigmentation.

1:01:49Steven Gundrysupportedmoderate

Polyphenols act as prebiotics.

"And really interestingly, polyphenols are of themselves prebiotics." (said at 1:01:49)

Dietary polyphenols are recognized in nutritional science as possessing prebiotic activity. Under the 2017 International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus definition, a prebiotic is defined as 'a substrate that is selectively utilized by host microorganisms conferring a health benefit', which explicitly expanded the concept beyond traditional non-digestible oligosaccharides to include non-carbohydrate compounds such as polyphenols. Most ingested polyphenols reach the colon intact, where they are selectively biotransformed and metabolized by specific gut microbes, promoting beneficial bacterial taxa and contributing to metabolic and immune health.

1:00:49Steven Gundrysupportedmoderate

Traditional societies have greater gut microbiome diversity compared to modern industrialized societies.

"I think if people have a really great, diverse microbiome like traditional societies do, these lectin-containing foods can be handled better than our society where we have a worthless microbiome" (said at 1:00:49)

Comparative metagenomic and 16S rRNA sequencing studies consistently demonstrate that traditional and non-industrialized populations (including hunter-gatherer and traditional agrarian communities) possess significantly higher gut microbiome alpha-diversity and harbor bacterial taxa absent in modern industrialized populations.

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.