HoldsUp

FoundMyFitness · 2016-05-03 · Rhonda Patrick (host), Ray Cronise

Ray Cronise on Cold Thermogenesis, Intermittent Fasting, Weight Loss & Healthspan

47 claims checked against research: 8 contradicted 1 contradicted online 3 overstated 3 needing context 25 supported 7 unverified

8

Contradicted by research

0:06:05Ray Cronisecontradictedmoderate

Alanine levels increase significantly during prolonged fasting because it is primarily utilized for gluconeogenesis.

"Of course, things like alanine, which is mainly used for gluconeogenesis, went through the roof; lipids go through the roof." (said at 0:06:05)

The claim is contradicted by physiological evidence regarding amino acid metabolism during fasting. While alanine is indeed the principal gluconeogenic amino acid extracted by the liver, circulating plasma alanine levels do not increase ("go through the roof") during prolonged fasting; instead, they drop precipitously. Classic metabolic studies in humans show that preferential hepatic uptake of alanine for gluconeogenesis rapidly depletes circulating levels, leading to sustained hypoalaninemia. In contrast, branched-chain amino acids (leucine, isoleucine, valine) and lipid metabolites (free fatty acids and ketone bodies) rise during fasting.

  • contradicts: Amino acid metabolism during prolonged starvation. (The Journal of clinical investigation 1969) · cited 724x in the literature
    "It is concluded that the marked decrease in plasma alanine is due to augmented and preferential splanchnic utilization of this amino acid in early starvation resulting in substrate depletion. Maintenance of the hypoalaninemia ultimately serves to diminish splanchnic uptake of this key glycogenic amino acid and is thus an important component of the regulatory mechanism whereby hepatic gluconeogenesis is diminished and protein catabolism is minimized in prolonged fasting." (abstract, conclusions, passage verified)
    pubmedfull study (doi)
0:44:28Rhonda Patrick (host)contradictedmoderate

In animal models challenged with neurotoxins causing neuronal cell death, intermittent fasting is neuroprotective whereas dietary/caloric restriction is not.

"The one difference that was found in this paper—and I forgot which group it was that did this, and it's pretty recent—was that when they challenged the brain with some sort of neurotoxin that caused neuronal cell death, the intermittent fasting was protective, but the caloric restricted or dietary restricted was not." (said at 0:44:28)

The claim that caloric or dietary restriction is not neuroprotective in animal models challenged with neurotoxins causing neuronal cell death contradicts the published literature. Extensive preclinical and review literature demonstrates that both daily caloric restriction and intermittent fasting confer neuroprotection against excitotoxic neurotoxins and experimental brain injury by enhancing mitochondrial resistance, upregulating neurotrophic factors, and suppressing oxidative stress and apoptotic pathways.

1:03:39Ray Cronisecontradictedhigh

When measured as fat per calorie across all different cuts of meat, the fat content is between 25% and 30%, meaning there is no truly lean meat.

"Now if you report the fat per weight, it's the same, but if you report fat per calorie on all the different cuts of meat, we're all between 25–30%. There's no lean meat, they're all about the same, I mean they're very, very close." (said at 1:03:39)

The claim that fat accounts for 25% to 30% of total calories across all cuts of meat—and that there is no truly lean meat—is contradicted by standard nutritional analyses and nutrient data. Fat content and calorie percentage vary significantly across different cuts and species of meat. For instance, skinless chicken breast or turkey breast typically contains around 10% to 20% of total calories from fat (approx. 1–3 grams of fat per 100–165 calories), whereas untrimmed cuts or fatty processed meats can derive 50% or more of their total calories from fat. Furthermore, published analyses of lean meat cuts confirm that specific cuts qualify as lean under USDA standards (containing less than 10 g total fat, 4.5 g saturated fat, and 95 mg cholesterol per 100 g portion). Cuts such as beef tenderloin steak, top sirloin steak, and fresh-lean pork cuts derive a much lower proportion of calories from fat than untrimmed or high-fat cuts, demonstrating a wide variation rather than a uniform 25%–30% ratio.

1:20:52Ray Cronisecontradictedhigh

In clinically depressed patients, taking five-minute cold showers at 60 degrees Fahrenheit produced results as good as medications for depression.

"But like um on um clinic- clinically depressed patients, they were doing five-minute cold showers with 60 degrees F and and they were having as good as as good of results with medications with their depression." (said at 1:20:52)

The speaker claims that in clinically depressed patients, taking 5-minute cold showers at 60 degrees Fahrenheit produced results as good as antidepressant medications. This is contradicted by the published scientific literature. The original hypothesis proposing adapted cold showers (20°C / ~68°F for 2–3 minutes) as a potential treatment for depression (Shevchuk, 2008) was a theoretical paper published in *Medical Hypotheses* with no clinical trial, no control group, and only informal anecdotal testing in a small number of individuals who did not meet diagnostic criteria for depression. No clinical trial has shown that cold showers perform as well as antidepressant medications in clinically depressed patients.

1:22:25Ray Cronisecontradictedhigh

Non-shivering thermogenesis can produce a 300% to 500% increase in metabolic rate.

"and you go into your non-shivering thermogenesis. And yes, you boost up, you can get 300 to 500% increase in metabolic rate, and you can measure this" (said at 1:22:25)

In adult humans, cold-induced non-shivering thermogenesis (primarily mediated by brown adipose tissue activation and futile cycling in muscle) typically increases resting metabolic rate by approximately 10% to 30% above baseline. Increases of 300% to 500% (a 4- to 6-fold increase) can occur during intense muscular exercise or maximal shivering, or in small rodents during rewarming from torpor, but exceed the physiological capacity of human non-shivering thermogenesis by more than an order of magnitude.

1:29:03Ray Cronisecontradictedmoderate

Shivering burns carbohydrate as fuel rather than fat.

"And if you're shivering, you're burning carbohydrate, you're not burning fat, right? Shivering is exercise." (said at 1:29:03)

The claim that shivering burns carbohydrate rather than fat is contradicted by human physiological studies. During cold-induced shivering thermogenesis, both lipids (fats) and carbohydrates are oxidized to produce heat. In low- to moderate-intensity shivering, lipid oxidation increases substantially and accounts for approximately 50% of total heat production, with muscle glycogen, plasma glucose, and protein supplying the remainder. While the proportional reliance on carbohydrate (specifically muscle glycogen) rises at higher shivering intensities, fat oxidation remains a significant contributor to energy expenditure during cold exposure.

1:53:42Rhonda Patrick (host)contradictedmoderate

Most melatonin synthesized in the human body is produced in the gastrointestinal tract from serotonin.

"The other interesting thing is that most of the melatonin made in the body is actually made in the gut, right? Serotonin gets converted into melatonin" (said at 1:53:42)

While serotonin is the biochemical precursor to melatonin, the claim that most of the body's melatonin is produced in the gastrointestinal tract is contradicted by modern evidence. For decades, literature frequently cited a 1992 report proposing that the gastrointestinal tract contained 400 times more melatonin than the pineal gland. However, rigorous modern evaluation demonstrates that early estimates relied on unvalidated immunoassays affected by cross-reactivity with tryptophan metabolites. Contemporary quantitative measurements show that the ratio of duodenal to pineal melatonin content is actually between 0.05:1 and 0.19:1, and surgical pinealectomy effectively eliminates circulating melatonin, establishing that the gut is not a primary source of systemic melatonin synthesis in mammals.

1:33:21Ray Cronisecontradictedmoderate

Bernarr Macfadden was the first to link diet and exercise primarily through the calorie between 1900 and 1911.

"because this all got started around 1911. Well, between 1900, 1911, McFadden was the first one. I'll show you the books in the room where all this got together, and the link of diet and exercise happened primarily through the calorie." (said at 1:33:21)

Historical scholarship on nutritional science and physical culture contradicts the claim that Bernarr Macfadden was the first to link diet and exercise primarily through the calorie between 1900 and 1911. The scientific quantification of human energy balance and dietary calories was established earlier in the late 19th century by nutritional scientists such as Wilbur Olin Atwater, while the popularization of calorie counting for weight management emerged primarily in the late 1910s and 1920s through figures like Dr. Lulu Hunt Peters (author of the 1918 bestseller 'Diet & Health: With Key to the Calories'). While Macfadden was a prominent physical culture entrepreneur during the early 1900s who emphasized exercise and nutrition, his dietary philosophies focused on fasting, whole foods, and natural vitality rather than pioneering calorie-based energy accounting.

1

Contradicted by web sources

0:11:05Ray Cronisecontradicted (web)

At the turn of the 20th century, the average person spent 60% of their income on food.

"if you think about the average person was spending 60% of their income on food." (said at 0:11:05)

No published record matching the claim that the average person spent 60% of their income on food at the turn of the 20th century was located; this does not prove the claim false.

contradicted by web sources

According to historical data from the U.S. Bureau of Labor Statistics, average households spent approximately 42.5% of their expenditures on food at the turn of the 20th century in 1901, rather than 60%. While basic necessities as a whole accounted for roughly 80% of spending, food alone was well below 60%.

bls.govhumanprogress.org

3

Overstated

0:09:05Ray Croniseoverstatedvery low

Essential amino acids such as methionine increase fecundity but are negatively associated with longevity.

"I mean, you guys are in prime reproduction time, so to get fecundity to go up, we want to increase essential amino acids. We know that things like methionine, whatever, increase fecundity. At the same time, where I am, which I'm done with that process at 51, I want to make sure of longevity, and they're also negatively associated with longevity." (said at 0:09:05)

The trade-off between reproduction (fecundity) and lifespan mediated by essential amino acids and methionine is a well-established phenomenon in laboratory model organisms (such as Drosophila melanogaster and rodents), but direct evidence demonstrating that manipulating dietary methionine or essential amino acids modulates fecundity and human longevity is lacking. In model organisms, restricting protein or methionine extends lifespan, whereas supplementing essential amino acids generally enhances reproductive output at the expense of lifespan.

1:51:41Ray Croniseoverstatedmoderate

Pineal gland melatonin secretion begins to decline precipitously around age 40.

"and I'm getting old—obviously past 40, my melatonin is falling off precipitously at this point, you know, that's what all the studies say." (said at 1:51:41)

Melatonin production and nighttime peak amplitudes do decrease with age across the human lifespan, but the literature shows that this decline is gradual or occurs much earlier in life (during childhood and young adulthood before age 30), rather than a "precipitous" cliff starting around age 40. A comprehensive review and analysis of urinary metabolite (6-sulfatoxymelatonin) and plasma melatonin data found that age-related declines occur primarily between childhood and ages 20–30, with little significant difference among groups beyond age 35. While some studies show reduced nocturnal salivary melatonin amplitude in middle-aged adults compared to young adults, the characterization that melatonin levels "fall off precipitously" beginning specifically around age 40 overstates both the rate of change and its onset timing.

1:54:25Ray Croniseoverstatedlow

Studies from the 1930s showed Australian Aborigines were able to achieve normal REM sleep in sub-freezing (30-degree) conditions without blankets, while Caucasian controls were unable to adapt.

"Now, these are like the Aboriginal studies that were done, these are I think in the '30s or whatever, where they took little refrigerated trucks into Australia, took the natives who, by culture, they sleep under 30-degree temperature, no covers, no blankets. They shiver all night and they get perfect REM sleep. And yet the Caucasian control, those guys were just miserable and they were horrible." (said at 1:54:25)

Classics studies led by Per Scholander and colleagues in the 1950s investigated cold adaptation in Central Australian Aborigines sleeping exposed to near-freezing or cold ambient temperatures (often around 0°C to 5°C). The research demonstrated that Central Australian Aborigines exhibited an insulative-hypothermic type of cold adaptation: compared to white European controls, Aboriginal participants fell asleep without shivering, allowing their body temperature (and metabolic rate) to drop slightly while maintaining uninterrupted sleep. In contrast, unacclimated Caucasian control subjects shivered intensely, reported severe discomfort, and were unable to sleep restfully. However, the speaker overstates and mischaracterizes key aspects of these studies: the classic field research was conducted primarily in the late 1950s (not the 1930s), used custom field tents/equipment (not refrigerated trucks), and did not measure or document 'perfect REM sleep' (electroencephalography and REM sleep stages were not recorded in these field studies; sleep was evaluated via physiological tolerance, skin and core temperature recordings, and metabolic monitoring).

3

Needs context

0:22:33Rhonda Patrick (host)needs contextmoderate

The gastrointestinal tract contains the highest concentration of immune cells in the human body.

"the number one driver of inflammation in humans in our bodies is the gut. Yes. The gut is where we have the highest concentration of immune cells." (said at 0:22:33)

In medical and immunological literature, the gastrointestinal tract (via the gut-associated lymphoid tissue, or GALT) is widely described as the largest immune organ in the human body, serving as the principal site of antigen exposure and housing a massive population of mucosal immune cells, including plasma cells, intraepithelial lymphocytes, and macrophages. However, quantitative cell censuses of the whole human body (such as Sender et al., 2023) show that by absolute cell numbers and density, the primary pools of lymphocytes reside predominantly in the lymph nodes and spleen, while the majority of neutrophils reside in the bone marrow. Characterizing the gut as having the single 'highest concentration' of immune cells is therefore contextually valid in the sense of mucosal immunological mass and daily immune activity, but slightly imprecise when comparing baseline cellular distributions across primary lymphoid organs.

0:32:23Ray Croniseneeds contextmoderate

Mild cold stress naturally lowers the respiratory quotient (RQ), shifting substrate utilization toward fat oxidation.

"it turns out mild cold stress naturally tends to lower your RQ, meaning shifting towards fat." (said at 0:32:23)

Mild cold exposure (above the shivering threshold) can promote lipid utilization and non-shivering thermogenesis mediated by brown adipose tissue and skeletal muscle, and changes in thermoregulatory mediators like irisin correlate with lower respiratory quotient (RQ) and higher fat oxidation. However, whole-body indirect calorimetry studies indicate that this shift is not universal: controlled 24-hour trials of mild cold (e.g., 19 °C) found no significant overall decrease in 24-hour respiratory exchange ratio (RER) across all participants, and cold-induced metabolic flexibility varies considerably by ethnicity and individual metabolic status. Furthermore, if cold stress becomes severe enough to induce shivering, substrate utilization shifts heavily toward carbohydrate oxidation rather than fat oxidation.

0:43:37Rhonda Patrick (host)needs contextmoderate

Human insulin resistance reaches its highest levels around 10:00 PM due to circadian regulation.

"And you're the most insulin resistant at 10:00 o'clock at night, and they have problems with metabolism problems and weight loss and all these things." (said at 0:43:37)

Human glucose tolerance and insulin sensitivity follow a robust circadian rhythm, exhibiting peak insulin sensitivity in the biological morning/noon and a marked decline in insulin sensitivity (i.e., increased insulin resistance) during the biological evening and night. However, pinning the peak to exactly 10:00 PM oversimplifies circadian physiology, as the exact nadir of insulin sensitivity varies between individuals based on chronotype, habitual sleep-wake schedules, and endogenous melatonin onset (typically spanning late evening to biological midnight).

25

Supported by research

0:07:15Rhonda Patrick (host)supportedhigh

Bruce Ames proposed the triage theory, positing that when micronutrients are limited, the body prioritizes proteins required for short-term survival over those required for long-term health and DNA maintenance.

"and this is something that my mentor, Bruce Ames, has proposed and put out there, and I know that you're familiar with something that he calls triage theory—and that is, well, there's all these enzymes and proteins that require some of these micronutrients as cofactors that are not essential for short-term survival. So if you're deficient in it, it doesn't matter right now because it's not needed right now; it's needed for a long-term survival. It's needed to repair damage that's constantly happening, right? It's needed to prevent things like cancer, Alzheimer's disease." (said at 0:07:15)

The speaker accurately summarizes the triage theory formulated and published by biochemist Bruce Ames. Under this hypothesis, when micronutrient supply is inadequate, the body preferentially allocates limited vitamins and minerals to enzymes and pathways critical for short-term survival and reproduction, while rationing them away from enzymes involved in long-term maintenance, DNA repair, and protection against chronic age-related diseases such as cancer and neurodegeneration.

0:20:28Rhonda Patrick (host)supportedmoderate

A study by a Japanese research group comparing elderly individuals, centenarians, and supercentenarians identified inflammation as the only biomarker inversely related to longevity across all age groups.

"a recent study has been published by this Japanese group where they looked at a variety of different biomarkers that are age-related. So they looked at—these scientists looked at telomere length, markers of senescence; they looked at hematopoiesis; they looked at glycated hemoglobin, blood glucose levels, insulin sensitivity; and they've looked at inflammatory cytokines, biomarkers of inflammation, biomarkers of all the inflammatory pathways. And they looked at it in three different populations of people: the elderly, which are about 85 to 90 years old; centenarians, which were 100 years old; and then semi-supercentenarians, which are like 105; and then supercentenarians, which were 110 up to 115... the only biomarker that was identified to drive the aging process in all three categories—the elderly, centenarians, semi—or all four, was inflammation, right? Inflammation was inversely related to longevity." (said at 0:20:28)

A 2015 prospective cohort study by a Japanese research group (Arai et al., combining the TOOTH, Tokyo Centenarians Study, and Japanese Semi-Supercentenarians Study cohorts; n = 1,554) evaluated various age-related biomarker domains, including inflammation, hematopoiesis, lipid and glucose metabolism, renal/liver function, and telomere length/cellular senescence across the very old (85-99 years), centenarians, and semi-supercentenarians (105+ years). The investigators found that inflammation was the primary biomarker domain predicting all-cause mortality and cognitive/functional capability across age groups up to extreme old age, whereas telomere length and other domains were not independent predictors.

  • supports: Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Lo… (EBioMedicine 2015) · cited 332x in the literature
    "We combined z scores from multiple biomarkers to describe haematopoiesis, inflammation, lipid and glucose metabolism, liver function, renal function, and cellular senescence domains. In Cox proportional hazard models, inflammation predicted all-cause mortality with hazard ratios (95% CI) 1.89 (1.21 to 2.95) and 1.36 (1.05 to 1.78) in the very old and (semi-)supercentenarians, respectively... Centenarians and their offspring were able to maintain long telomeres, but telomere length was not a predictor of successful ageing in centenarians and semi-supercentenarians. We conclude that inflammation is an important malleable driver of ageing up to extreme old age in humans." (abstract, results and conclusions, passage verified)
    pubmedfull study (doi)
0:22:14Rhonda Patrick (host)supportedhigh

The average lifespan in the United States is approximately 79 years.

"if you look at the average lifespan in the US, it's 79, so close to 80." (said at 0:22:14)

According to official mortality data from the National Center for Health Statistics (NCHS) and the CDC, life expectancy at birth in the United States was 78.8 years in 2019, declined to 77.0 years in 2020 during the COVID-19 pandemic, and rebounded to 77.5 years in 2022 and 78.4 years in 2023. Describing the average lifespan in the United States as approximately 79 years is consistent with national vital statistics.

0:41:01Rhonda Patrick (host)supportedmoderate

Insulin sensitivity peaks in the morning due to the circadian rhythm of metabolic enzymes.

"so in the morning you are the most insulin sensitive in the morning, you know? So the way our metabolic enzymes—they're going on a rhythm." (said at 0:41:01)

Human clinical trials and mechanistic physiological studies confirm that insulin sensitivity and glucose tolerance follow a circadian rhythm and peak in the morning compared to the evening. Studies using hyperinsulinemic-euglycemic clamp procedures and oral glucose tolerance tests demonstrate higher skeletal muscle insulin sensitivity and superior overall glucose tolerance in the morning, governed by circadian clock gene expression (such as Per2), cortisol rhythms, and diurnal metabolic enzyme pathways.

0:42:10Ray Cronisesupportedmoderate

Eating starches in the evening results in slower blood glucose clearance and prolonged glucose tailing compared to earlier in the day.

"If you're eating starches in the evening, instead of getting those sharp peaks that you saw today, you'll get tailing. So this is true. I mean, there's no doubt that you'll get tailing. The glucose doesn't clear as fast the later in the evening." (said at 0:42:10)

Human circadian physiology trials consistently demonstrate that carbohydrate and starch consumption in the evening results in reduced glucose tolerance, decreased early-phase insulin secretion, and slower glucose clearance compared to morning consumption. This manifests as sustained postprandial hyperglycemia and prolonged clearance curves ('tailing') rather than the rapid peak and return to baseline typical of earlier meals.

0:47:35Ray Cronisesupportedvery low

The longest medically supervised water fast recorded in published literature was 382 days, during which the patient lost 276 pounds and reached 185 pounds while taking only multivitamins and intermittent electrolytes.

"the longest medically supervised water fast was 382 days. HOST: And that—382 days? GUEST1: Yeah, 382. He lost 276 pounds in 382 days. I'll send you the paper. Actually, I might have even posted it up on your thing, but it's 382 days medically supervised. HOST: No supplements or anything? GUEST1: They did a multivitamin and then in the middle, 49 days, they had to do some electrolytes, but other than that it was fine, and he weighed 185 when he was done." (said at 0:47:35)

The speaker accurately describes a famous 1973 single-case report by Stewart and Fleming published in the Postgraduate Medical Journal (PMID 4803438). The report documents a 27-year-old male patient who underwent a medically supervised fast of 382 days, starting at 456 lb (207 kg) and ending at 180 lb (81.6 kg), losing 276 lb. Management included daily multivitamins, vitamin C, potassium supplements when plasma levels dropped, and sodium later in the fast. As this is a single case report describing an extraordinary clinical protocol, the certainty of evidence for general application is very low.

0:58:42Rhonda Patrick (host)supportedmoderate

When humans practice dietary restriction, they tend to compensate by increasing protein intake, which subsequently prevents IGF-1 levels from decreasing.

"And then they figured out humans, when they're dietary restricted, tend to eat more protein because it's more satiating, and then you're like, "Oh, so then their IGF-1 levels were going high,"" (said at 0:58:42)

The claim accurately reflects findings from clinical studies investigating human calorie restriction (CR). Unlike in rodents, where calorie restriction consistently lowers circulating IGF-1, long-term calorie restriction in humans does not significantly lower serum IGF-1 levels if protein intake remains high. In studies of individuals practicing long-term CR, participants maintained high protein intakes (averaging ~1.67 g/kg body weight/day), and their IGF-1 levels remained comparable to controls. Only when protein intake was specifically restricted (to ~0.95 g/kg/day for 3 weeks) did circulating IGF-1 levels significantly drop.

0:47:10Rhonda Patrick (host)supportedmoderate

Senescent cells secrete signaling molecules and factors that cause damage to neighboring cells.

"those dysfunctional cells, as you call them, they're often senescent, which means they're not dead, they're not alive, they're sitting around. And what are they doing? They're secreting hormones, they're damaging neighboring cells." (said at 0:47:10)

The host's description of cellular senescence is biologically accurate. Senescent cells enter an essentially irreversible state of cell-cycle arrest (they remain metabolically active rather than dead) and develop the senescence-associated secretory phenotype (SASP). Through the SASP, senescent cells secrete a wide range of pro-inflammatory cytokines, chemokines, growth factors, and proteases. These secreted factors act via paracrine signaling to induce tissue inflammation, dysfunction, malignant transformation, and 'secondary senescence' (paracrine senescence) in neighboring healthy cells.

0:38:04Ray Cronisesupportedmoderate

Blending plant foods ruptures cell walls to increase bioavailability and access to cellular nutrients compared to whole plants.

"blending certainly ruptures the cells, certainly get more access." (said at 0:38:04)

Evidence from human trials and in vitro digestion studies demonstrates that intact plant cell walls physically encapsulate intracellular nutrients, limiting the penetration of digestive enzymes and the release (bioaccessibility) of cellular contents. Mechanical disruption, such as blending, milling, or fine processing, ruptures the cell walls, directly increasing the release and bioavailability of intracellular macronutrients and micronutrients compared to intact whole plant tissues.

1:02:33Ray Cronisesupportedhigh

Chitin found in crab shells is a carbohydrate.

"Chitin in crab shells, carbohydrate." (said at 1:02:33)

Chitin is a long-chain polysaccharide (carbohydrate) composed of repeating β-(1,4)-N-acetyl-D-glucosamine units. It serves as a major structural component in the exoskeletons of crustaceans, including crab and shrimp shells, and is the second most abundant natural polysaccharide after cellulose.

1:05:35Rhonda Patrick (host)supportedvery low

Valter Longo's research in mice demonstrates that 48 hours of intermittent fasting robustly activates autophagy and increases hematopoiesis.

"And from Valter Longo's research at USC, at least in animals and mice, he's shown that it takes 48 hours of intermittent fasting to activate that whole autophagy system robustly and to increase hematopoiesis." (said at 1:05:35)

Valter Longo's laboratory at USC published landmark animal research in mice demonstrating that prolonged fasting (typically 48 to 72 hours in mice) lowers circulating IGF-1 and PKA signaling, promoting hematopoietic stem cell (HSC) self-renewal, lineage-balanced regeneration (hematopoiesis), and stress-response pathways such as autophagy. Because this claim describes findings from mouse models and preliminary mechanistic data, the body of clinical evidence for human application remains very low certainty, though the speaker's description of Longo's animal findings is accurate.

1:08:35Rhonda Patrick (host)supportedmoderate

The FOXO3 gene is well known to be associated with longevity and supercentenarians.

"We know, for example, FOXO3 is one that's well known to be associated with—" (said at 1:08:35)

Multiple large-scale genetic studies and meta-analyses confirm that polymorphisms within the FOXO3 (FOXO3A) gene are consistently associated with exceptional human longevity and reaching centenarian status across diverse populations. Meta-analyses examining long-lived cohorts (including centenarians and semi-supercentenarians) replicate significant associations for several FOXO3 single-nucleotide polymorphisms (SNPs), such as rs2802292 and rs2764264, with extreme survival.

1:11:12Ray Cronisesupportedlow

Cold stress and dietary restriction hit the same genes, including UCP1 and PGC-1alpha.

"and what we have in our Metabolic Winter hypothesis paper is the fact that these two traits, cold stress and dietary restriction, hit the same genes, hit the same UCP1, hit the same PGC-1alpha." (said at 1:11:12)

The speaker accurately describes the premise of the 'metabolic winter' hypothesis, which posits that cold stress and dietary/caloric restriction engage overlapping cellular and metabolic pathways. Preclinical and molecular studies confirm that both cold exposure and caloric restriction upregulate shared regulatory programs controlling thermogenesis and mitochondrial biogenesis in adipose tissue, notably uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha).

1:13:22Rhonda Patrick (host)supportedhigh

Cryotherapy and cold water immersion have been shown to stimulate the release of norepinephrine.

"and I know that's, you know, norepinephrine's being released. It's been shown with cryo and cold water immersion." (said at 1:13:22)

The claim is supported by scientific evidence. Studies evaluating physiological responses to cold exposure show that both whole-body cryotherapy and cold water immersion trigger marked increases in circulating norepinephrine (noradrenaline) levels. For example, a trial investigating whole-body cryotherapy at -110 °C observed a significant acute rise in plasma norepinephrine following exposure (Poirier et al., 2020). Similarly, research evaluating head-out cold water immersion at 14 °C documented a 530% increase in plasma norepinephrine concentrations (Srámek et al., 2000). A study directly comparing 12-week protocols of winter swimming (water 0–2 °C) and whole-body cryotherapy (air -110 °C) found sustained 2- to 3-fold increases in plasma norepinephrine following exposure to both modalities (Leppäluoto et al., 2008).

1:24:18Ray Cronisesupportedmoderate

When a person experiences a muscle pump in the gym, the volume increase is due to added fluid rather than newly added protein or amino acids.

"So like, for example, when you pump up in a gym, you're not adding protein or any amino acids, you're just adding fluid." (said at 1:24:18)

The claim is supported. Acute exercise-induced muscle swelling—commonly referred to as a "muscle pump" or transient hypertrophy—is driven by hyperemia and acute fluid shifts from the plasma into intracellular and extracellular muscle compartments during and immediately after exercise, rather than by acute accretion of new protein or amino acids.

1:29:24Ray Cronisesupportedmoderate

Exercise stimulates the production of irisin, which upregulates and creates more brown adipose tissue.

"they start to exercise, they produce irisin. Irisin is known to upregulate and create more brown adipose tissue, and we've seen this happen." (said at 1:29:24)

Exercise stimulates skeletal muscle to express PGC-1α and cleave the membrane protein FNDC5 into the circulating myokine irisin. In preclinical models and cellular studies, irisin directly stimulates the browning of white adipose tissue—upregulating uncoupling protein 1 (UCP1) and thermogenic gene expression to create brown-fat-like (beige) adipocytes. Systematic reviews and meta-analyses in humans also show that both acute and chronic exercise modalities elevate circulating irisin levels.

1:30:22Ray Cronisesupportedhigh

In non-shivering thermogenesis, UCP1 causes proton-electron leaks through the mitochondria to produce 100% heat without generating ATP, utilizing lipids as the fuel source.

"non-shivering thermogenesis kicks in, upregulation happens, UCP1, now I'm just using, you know, proton-electron leaks through the mitochondria, and suddenly I'm not producing ATP, I'm just producing 100% heat. What's the cell using to do that? It's it's grabbing the most energy-dense fuel and is using lipids to do it." (said at 1:30:22)

The core mechanism described by the speaker is well established in mitochondrial bioenergetics. Uncoupling protein 1 (UCP1), located in the inner mitochondrial membrane of brown adipose tissue, facilitates non-shivering thermogenesis. UCP1 is activated by free fatty acids (lipids) and catalyzes a regulated proton leak back across the inner mitochondrial membrane. This uncouples nutrient oxidation from the F0F1-ATP synthase, dissipating the electrochemical proton gradient directly as heat rather than storing it as ATP. While the speaker casually mentions 'proton-electron leaks', UCP1 specifically transports protons (H+) across the membrane.

1:31:33Rhonda Patrick (host)supportedvery low

Midlife aerobic exercise in mice prevents blood-brain barrier breakdown and decreases the amount of activated microglia.

"like a study just I was reading today about on the brain, how it's like doing aerobic exercise in midlife for a mouse, like, prevented the blood-brain barrier from breaking down, prevented, decreased the amount of activated microglia, you know." (said at 1:31:33)

The claim accurately reflects findings from animal research. A 2015 mouse study demonstrated that voluntary aerobic exercise initiated at midlife and continued into old age prevented age-related neurovascular decline (including vascular leakage and breakdown of neurovascular structures) and reduced the upregulation of complement-activated (C1QA+) microglia/monocytes. However, because this evidence is derived exclusively from rodent models, the certainty of evidence for human translation is very low.

1:03:00Ray Cronisesupportedhigh

Following the McGovern Report, United States government food policy adopted a pattern of naming specific whole foods when recommending increased intake ('eat more fruits and vegetables') but only naming nutrient categories rather than specific foods when recommending reductions ('eat less saturated fat, eat less oils, eat less refined sugars').

"We have the "eat more, eat less" policy in the United States. It came out after the McGovern Report, which basically is when we're going to say something good about food from a government perspective: eat more fruits, eat more vegetables. If it's something that's bad, we're not allowed to name the food: eat less saturated fat, eat less oils, eat less refined sugars." (said at 1:03:00)

Historical and policy analysis of United States dietary guidelines confirms the speaker's account. When the Senate Select Committee on Nutrition and Human Needs (chaired by Senator George McGovern) released the initial 'Dietary Goals for the United States' in February 1977, it explicitly recommended that Americans 'decrease consumption of meat'. Following fierce opposition from the cattle, egg, and dairy industries, the committee published a revised edition later that year altering the wording to nutrient-based language (e.g., choosing meats that 'reduce saturated fat intake'). Subsequent federal dietary guidance, including the Dietary Guidelines for Americans published jointly by the USDA and HHS, established an enduring precedent of promoting specific foods when encouraging consumption ('eat more fruits and vegetables') while using abstract biochemical or nutrient terms ('reduce saturated fat, sodium, added sugars') to avoid advising against purchasing specific agricultural commodities.

1:33:51Ray Cronisesupportedmoderate

Physical exercise stimulates the production of irisin, which causes tissue to burn fuel and generate waste heat.

"It doesn't make sense for the body to create irisin that creates a tissue that burns fuel and just creates waste heat unless it had unless it was more energetically—to do it, it was more energetically to get up and move to create the waste heat to go get something, that would have probably been the pathway." (said at 1:33:51)

Published literature supports the claim that physical exercise induces the secretion of irisin, an exercise-induced myokine that promotes the browning of white adipose tissue and upregulates uncoupling protein 1 (UCP1), leading to increased thermogenesis and energy expenditure. Seminal research demonstrated that exercise stimulates PGC-1α expression in muscle, triggering the cleavage and secretion of irisin, which drives brown-fat-like phenotypic changes in adipose tissue and elevates energy expenditure. Systematic reviews and meta-analyses in humans confirm that exercise protocols significantly increase circulating irisin levels.

1:39:08Rhonda Patrick (host)supportedvery low

An animal study showed that aerobic exercise in midlife delayed markers of Alzheimer's disease in the brain.

"So this animal study I just told you that was just published in FASEB Journal, I believe, or maybe it was PLOS... It's one of the, I'm sorry, I don't remember which journal, but it was published like today, where they showed that in midlife, you know, aerobic exercise had all these positive effects in the brain, delayed, you know, markers of Alzheimer's and all this stuff." (said at 1:39:08)

Animal research supports the claim that aerobic exercise initiated in midlife delays neuropathological markers, neurovascular decline, and cognitive deficits related to Alzheimer's disease. In mouse models, long-term voluntary running or aerobic exercise from midlife onward preserves neurovascular integrity, stabilizes apolipoprotein E (ApoE), reduces neuroinflammatory complement activation, and lowers hippocampal levels of Alzheimer's markers such as amyloidogenic fragments and phosphorylated tau. Because the evidence is derived from rodent models, the overall GRADE certainty for direct human translation is very low.

1:39:30Rhonda Patrick (host)supportedvery low

A Nature study showed that cold stress protected against Alzheimer's disease in transgenic animal models when applied in early life, but had no protective effect when applied in midlife.

"There's another study that was published about last year in Nature that showed that cold stress—it was mild cold stress, actually it was more than mild because—... But it showed that mild cold stress protected against Alzheimer's disease in animal models that were genetically engineered to get Alzheimer's, human Alzheimer's. It showed that it protected against it, but only if the cold stress was done in early life. So if the cold stress was done in midlife and not in early life, it had no protective effect." (said at 1:39:30)

A 2015 study published in Nature evaluated the neuroprotective effects of cooling (mild therapeutic hypothermia) in mouse models of neurodegenerative disease, including 5XFAD transgenic Alzheimer's disease mice. The authors found that cooling induced the cold-shock protein RBM3 and protected against synapse loss, behavioral deficits, and neuronal loss, but only when applied early in the disease course before endogenous RBM3 responsiveness was lost. Cooling applied at later disease stages failed to induce RBM3 and did not provide neuroprotection. Because the evidence is derived entirely from animal models, the certainty of evidence for translation to humans is very low.

  • supports: RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration… (Nature 2015) · cited 258x in the literature
    "In both prion-infected and 5XFAD (Alzheimer-type) mice, the capacity to regenerate synapses after cooling declined in parallel with the loss of induction of RBM3. Enhanced expression of RBM3 in the hippocampus prevented this deficit and restored the capacity for synapse reassembly after cooling. RBM3 overexpression, achieved either by boosting endogenous levels through hypothermia before the loss of the RBM3 response or by lentiviral delivery, resulted in sustained synaptic protection in 5XFAD mice and throughout the course of prion disease, preventing behavioural deficits and neuronal loss and significantly prolonging survival." (abstract, results, passage verified)
    pubmedfull study (doi)
1:42:15Ray Cronisesupportedmoderate

Combining cold stress with a calorie-restricted diet shifts the respiratory quotient (RQ) toward 0.7, indicating a shift toward fat oxidation.

"It definitely shifts your RQ, and what I have seen is that, generally speaking, after a few weeks of cold stress and doing a restrictive diet where you're just running at a chronic deficit, you're going to see your RQ shift more towards 0.7. It lowers, it goes more towards fat burning." (said at 1:42:15)

The speaker's statement accurately reflects well-established metabolic physiology. The respiratory quotient (RQ) represents the ratio of carbon dioxide produced to oxygen consumed: pure carbohydrate oxidation yields an RQ of approximately 1.0, whereas pure fat oxidation yields an RQ of approximately 0.70 to 0.71. Both caloric restriction (fasting/energy deficit) and cold exposure increase reliance on lipid metabolism and thermogenesis, thereby lowering the RQ toward ~0.7.

1:48:27Rhonda Patrick (host)supportedhigh

Administering melatonin to humans causes core body temperature to decrease.

"But one of the roles of melatonin is to have you drop core body temperature through your extremities. HOST: You actually told me that. You're the first person that told me that when we met a couple months ago, and I was completely fascinated and I looked at the studies. Yeah, administering melatonin to people does make their core body temperature drop." (said at 1:48:27)

Exogenous melatonin administration in humans reliably induces a decrease in core body temperature (a hypothermic effect). Randomized controlled and clinical trials demonstrate that administration of oral melatonin produces a statistically significant drop in core body temperature (typically around 0.15°C to 0.3°C at doses between 1.0 and 5.0 mg), which is closely associated with increased distal vasodilation and reduced sleep onset latency.

1:51:41Ray Cronisesupportedvery low

Research shows a synergistic activation effect between melatonin, resveratrol, and SIRT1.

"which is basically SIRT1 and melatonin and resveratrol all working together, so they found a synergistic effect with melatonin and SIRT1, melatonin and resveratrol and SIRT1." (said at 1:51:41)

Preclinical studies have investigated the combined application of melatonin and resveratrol on sirtuin 1 (SIRT1) expression. In animal and in vitro models, combining melatonin and resveratrol demonstrated synergistic effects on enhancing SIRT1 expression and activating downstream pathways (such as the SIRT1/FOXO3a/BCL2 signaling axis) compared to single-agent treatments. However, evidence remains limited to preclinical experimental models, with no clinical trial data in humans.

7

No source found (not proven false)

0:16:25Rhonda Patrick (host)unverifiedvery low

NHANES data show that many people in the US consume inadequate levels of essential micronutrients like folate, vitamin K, and selenium despite consuming excess calories.

"according to a lot of these NHANES studies coming out, getting inadequate levels of many of these micronutrients. You'd think if you're overnourishing yourself that you then would have adequate levels of micronutrients, but the thing is people are eating the wrong food. They're eating the wrong foods, and so they're not getting all their folate, vitamin K, selenium; they're not getting all these important micronutrients." (said at 0:16:25)

No published record matching the claim that NHANES data show widespread inadequate levels of folate, vitamin K, and selenium despite excess calorie intake was located; this does not prove the claim false.

0:27:50Ray Croniseunverifiedvery low

The respiratory quotient (RQ) for ethanol metabolism is approximately 0.67, for carbohydrates is 1.0, for fats is 0.69 to 0.70, and for amino acids averages 0.84.

"you'll see that, you know, you get a two on one side, three on the other, and you do the two and then three, and you get the respiratory quotient of 0.67... Carbohydrates of all types, doesn't matter what kind they are, all of the glucose, anything that's dropping in there, those have a respiratory quotient about 1. And then fats or lipids all run between 0.69 and 0.7. So what's really interesting is that amino acids, they average 0.84 if I average all of them." (said at 0:27:50)

No published record matching the claim regarding the specific respiratory quotient values for ethanol (0.67), carbohydrates (1.0), fats (0.69–0.70), and amino acids (averaging 0.84) was located; this does not prove the claim false.

0:51:59Ray Croniseunverifiedvery low

Eating food generates NADH, which directly shuts off SIRT1 activation.

"And SIRT1 gets activated every time you're making—so when you're eating anything, you know, when you're eating food you're going to make NADH, which shuts off SIRT1" (said at 0:51:59)

No published record matching the claim that eating food generates NADH which directly shuts off SIRT1 activation was located; this does not prove the claim false.

1:21:16Rhonda Patrick (host)unverifiedvery low

Cold exposure below 62 to 63 degrees Fahrenheit (17 degrees Celsius) increases norepinephrine levels.

"based on the fact that cold, if you're if you're—I think it's around 60, anything below 62 or 63 degrees Fahrenheit, 17 degrees Celsius, so yeah, it increases norepinephrine." (said at 1:21:16)

No published record matching the claim that cold exposure specifically below 62 to 63 degrees Fahrenheit (17 degrees Celsius) serves as a discrete threshold to increase norepinephrine levels was located; this does not prove the claim false.

1:22:00Ray Croniseunverifiedvery low

Mild cold stress begins at 80 degrees Fahrenheit in water and 60 degrees Fahrenheit in air, which is where metabolic and hormonal responses start to occur.

"mild cold stress begins at 80 F in water, okay? And it's uh it begins at 60 F in air. So that's about where the that's where you start seeing a change. You start seeing a metabolic response, you start seeing a hormonal hormonal response um at about those temperatures." (said at 1:22:00)

No published record matching the specific thresholds of 80°F in water and 60°F in air as the starting points for mild cold stress, metabolic changes, and hormonal responses was located; this does not prove the claim false.

1:28:20Ray Croniseunverifiedvery low

In a cold immersion test with journalist Steven Leckart in 70-degree Fahrenheit water, his respiratory quotient shifted from 1.0 (glycogen burning) to nearly 0.7 (predominantly fat burning), and fat oxidation remained elevated for over an hour after exiting the water.

"And his respiratory quotient went from 1.0, which is most activities are burning glycogen, almost to 0.7, almost pure fat. And for over an hour, he was still burning fat." (said at 1:28:20)

No published record matching the claim of a cold immersion test in journalist Steven Leckart showing a respiratory quotient shift from 1.0 to 0.7 and sustained fat oxidation for over an hour post-exposure was located; this does not prove the claim false.

1:52:42Rhonda Patrick (host)unverifiedvery low

Melatonin regulates approximately 500 different human genes, representing roughly 2.5% of the human genome.

"HOST: Melatonin is a hormone, regulates 500 different genes. GUEST1: Yeah, I mean that's 2.5% of the human genome." (said at 1:52:42)

No published record matching the claim that melatonin specifically regulates approximately 500 human genes (or roughly 2.5% of the human genome) was located; this does not prove the claim false. While melatonin is well established to influence gene expression across various physiological pathways and circadian networks, specific genomic profiling attributing regulation of a discrete set of 500 genes or exactly 2.5% of the human genome to melatonin has not been documented in peer-reviewed literature.

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.