HoldsUp

FoundMyFitness · 2016-10-01 · Rhonda Patrick (host), Valter Longo

Valter Longo, Ph.D. on Fasting-Mimicking Diet & Fasting for Longevity, Cancer & Multiple Sclerosis

35 claims checked against research: 1 contradicted 1 needing context 30 supported 3 unverified

1

Contradicted by research

1:11:10Rhonda Patrick (host)contradictedmoderate

Acute aerobic exercise lowers circulating serum IGF-1 in humans.

"it's been shown in humans that ex- acute exercise, I think it was aerobic, lowers serum IGF-1, and I think it's because it's going to the muscle, also to the brain" (said at 1:11:10)

The claim that acute exercise lowers serum IGF-1 in humans is contradicted by the literature. In healthy humans, exercise typically stimulates the growth hormone (GH)-IGF-1 axis, leading to transient increases or stability in circulating IGF-1, rather than reductions. Systematic reviews and meta-analyses examining exercise-induced modulation of IGF-1 show that exercise increases circulating IGF-1 in healthy individuals, although reductions can be observed in specific clinical populations such as cancer patients.

1

Needs context

0:40:20Valter Longoneeds contextlow

By roughly day two of a fasting-mimicking diet, the body switches to a ketogenic mode burning visceral fat, the brain uses beta-hydroxybutyrate, and organs including the liver, heart, immune system, and oligodendrocytes shrink.

"the fasting-mimicking diet really by day two of the diet—and only by day two or so of the diet—the system starts switching to a ketogenic mode. You start burning visceral fat as your major source of energy, your brain starts moving from burning sugar to burning ketone bodies, you know, beta-hydroxybutyrate. So, as I said, everything starts shrinking: the immune system starts shrinking, the liver, the heart, even the oligodendrocytes, as we've shown in our multiple sclerosis paper." (said at 0:40:20)

The speaker describes physiological and cellular responses to a fasting-mimicking diet (FMD) developed in research by Valter Longo and colleagues. Preclinical and clinical studies confirm that prolonged fasting or multi-day FMD cycles induce a shift to ketogenesis, raising circulating beta-hydroxybutyrate, utilizing fat stores, and reducing circulating white blood cells. In animal models, fasting cycles cause reversible decreases in the mass of various organs (such as liver and spleen) through cell shrinkage and autophagy/apoptosis, followed by stem-cell-mediated regeneration during refeeding. In their multiple sclerosis model (Choi et al., 2016), FMD induced apoptosis of autoimmune T cells and stimulated oligodendrocyte precursor cell regeneration and remyelination. However, translating transient cellular depletion and organ mass fluctuations observed in rodent models into broad statements that human organs and oligodendrocytes 'shrink' requires qualification, as direct evidence for organ shrinkage and oligodendrocyte dynamics derives primarily from preclinical animal models.

30

Supported by research

0:01:53Valter Longosupportedlow

Biosphere 2 was the site of the first human study on calorie restriction.

"I was there when they went into Biosphere 2, which was this uh uh bubble essentially in Arizona where they did the first human study on on calorie restriction." (said at 0:01:53)

The claim is supported. Biosphere 2 (a sealed facility near Tucson, Arizona) was the site of the first well-monitored, long-term human study evaluating the physiological effects of severe calorie restriction in non-obese individuals. During the two-year closure (1991–1993), lower-than-expected food crop yields forced the eight crew members (including gerontologist Roy Walford) to consume a low-calorie (1,750–2,100 kcal/day), nutrient-dense diet. Published studies of the crew confirmed marked reductions in body mass, blood pressure, blood glucose, leukocyte count, and blood lipids, establishing human physiological responses similar to those observed in calorie-restricted animal models. Because the evidence comes from a small, non-randomized cohort (n=8), certainty for the biological outcomes is low.

0:04:07Valter Longosupportedlow

During periodic fasting, stem cells are activated, and the subsequent refeeding phase drives the rebuilding and regeneration of the system.

"when we we published on regeneration, the stem cells are turned on during fasting, but it is the refeeding that causes the rebuilding of the system, and so the most important part is the refeeding." (said at 0:04:07)

The speaker accurately describes published findings from their laboratory regarding the distinct roles of fasting and refeeding in stem cell activation and tissue regeneration. In preclinical mouse studies, cycles of prolonged fasting or fasting-mimicking diets (FMD) reduced organ size and white blood cell levels while downregulating IGF-1 and PKA signaling to prime and activate hematopoietic and other stem cells; the subsequent refeeding period triggered stem cell proliferation and multi-system cellular regeneration. However, the direct mechanistic demonstration of stem-cell-driven organ regeneration remains primarily established in animal models, with human studies largely restricted to pilot trials evaluating circulating biomarkers and safety.

0:05:58Valter Longosupportedvery low

In mice, approximately 40% of white blood cells are destroyed through apoptosis during four days of fasting, and that 40% is rebuilt within a few days of refeeding.

"for example, in a mouse, about 40% of the white blood cells are destroyed during this period of four days of fasting or so, and then that 40% is rebuilt within a few days of refeeding, right?" (said at 0:05:58)

Preclinical animal research led by Valter Longo's group demonstrated that cycles of prolonged fasting in mice lead to a substantial depletion of circulating white blood cells (via cell death/apoptosis) alongside reductions in IGF-1 and PKA signaling, followed by hematopoietic stem cell activation and rapid regeneration of the immune cell population upon refeeding. Because this finding is based on rodent experimental models, the certainty of evidence for this specific biological mechanism is very low.

0:06:41Valter Longosupportedmoderate

Prolonged fasting causes internal organs, including the liver and immune system, to shrink through atrophy, followed by regeneration upon refeeding.

"fasting is probably the most powerful, at least that that we could think of, um the most powerful way, particularly if it's prolonged, to shrink a system, let's say make the liver a lot smaller, make all these organs a lot smaller, the immune system, and then regenerate it, right?" (said at 0:06:41)

Preclinical studies demonstrate that prolonged fasting and fasting-mimicking diets cause temporary organ shrinkage (including reduction in liver size and depletion of white blood cells) followed by stem cell-driven regeneration upon refeeding. In mouse models, periodic cycles of prolonged fasting or fasting-mimicking diets decreased organ mass, which was restored during refeeding via activation of progenitor and stem cells in multiple systems, including the hematopoietic and immune systems.

0:08:48Valter Longosupportedvery low

Fasting in aged mice restores lymphocyte numbers toward youthful levels and shifts the myeloid-to-lymphoid cell ratio back toward a youthful profile.

"we found that uh that the lymphocytes number uh goes back to the more youthful level, and the ratio of myeloid cells to lymphocytes goes also back, not to the the the same level as during youth, but certainly uh moves in that direction." (said at 0:08:48)

The claim accurately reflects findings published in animal studies. Research demonstrated that multiple cycles of prolonged fasting in old mice reduced age-dependent myeloid bias by promoting hematopoietic stem cell regeneration and lineage balance, shifting the myeloid-to-lymphoid ratio back toward a youthful profile. Because the direct experimental support for this age-reversal effect on lineage balance relies on mouse models, the overall certainty grade is very low for human applications.

0:13:23Valter Longosupportedmoderate

In a human population aged 20 to 70 with elevated C-reactive protein, three cycles of the fasting-mimicking diet returned C-reactive protein levels to normal.

"we also saw it in the population, in the human population aged 20 to 70 where everybody that had high C-reactive protein came down, back down after three cycles of the FMD, came back down to the normal levels." (said at 0:13:23)

In a randomized clinical trial of 100 generally healthy participants aged 20 to 70 years (Wei et al., 2017), subjects underwent three monthly 5-day cycles of a fasting-mimicking diet (FMD). A stratified analysis of participants with elevated baseline risk factors showed that C-reactive protein (CRP) levels were significantly reduced and returned toward normal levels in those who started with elevated CRP.

0:18:09Rhonda Patrick (host)supportedhigh

Cancer has become the leading cause of death in the state of California, surpassing heart disease.

"I think actually recently according to the newest CDC data, the state of California, it's the leading cause of death. Um it trumped uh heart disease in the state of California" (said at 0:18:09)

According to vital statistics from the Centers for Disease Control and Prevention (CDC) and population mortality data, cancer surpassed heart disease as the leading cause of death in California (a transition that occurred in 2010 and has continued in subsequent years). This shift reflects an ongoing epidemiologic transition in the United States, driven by sharp declines in cardiovascular disease mortality alongside slower reductions in cancer mortality, particularly in higher-income states and counties.

0:23:09Valter Longosupportedvery low

In mouse cancer models, cancer-free survival is achieved only when fasting or fasting-mimicking diets are combined with chemotherapy, whereas each intervention alone is almost never curative.

"This is why in mice we see uh cancer-free survival, meaning that mice are free of cancer only when we combine the starvation or the fasting-mimicking diets with the with the chemotherapy. You almost never see it when we use each one alone, right?" (said at 0:23:09)

Preclinical mouse studies from Valter Longo's laboratory show that cycles of fasting or fasting-mimicking diets (FMD) synergize with chemotherapy to achieve long-term cancer-free survival in several rodent models (such as neuroblastoma and acute lymphoblastic leukemia), whereas fasting or chemotherapy alone delayed tumor progression or extended survival but rarely resulted in complete, cancer-free cures. Because these findings are derived entirely from animal models, the certainty of evidence for translational clinical efficacy is very low.

0:29:06Valter Longosupportedvery low

Lowering glucose through fasting forces cancer cells into a fasting-dependent anti-Warburg effect, shifting them toward mitochondrial oxidative phosphorylation and reactive oxygen species generation.

"we published a paper calling it the fasting-dependent anti-Warburg effect. And so basically, normally the cancer cells can rely on glucose, and once the glucose is lowered, they have no choice but to try to go back to oxidative phosphorylation and using the mitochondria to gain energy, because there is no other way around it, right?" (said at 0:29:06)

The speaker accurately describes the findings of a 2015 study published by their laboratory (Bianchi et al., PMID 25909219). In preclinical colorectal cancer models, short-term starvation (STS) down-regulated aerobic glycolysis and induced an 'anti-Warburg effect,' shifting cancer cells toward mitochondrial oxidative phosphorylation (increased Complex I and Complex II-dependent oxygen consumption) alongside elevated oxidative stress and impaired ATP synthesis. Because this mechanism was demonstrated in vitro and in animal cancer models, the body of clinical evidence for this specific metabolic shift in human patients remains very low certainty.

  • supports: Fasting induces anti-Warburg effect that increases respiration but reduces ATP-synthesis t… (Oncotarget 2015) · cited 182x in the literature
    "In CT26 cells, STS down-regulated aerobic glycolysis, and glutaminolysis, while increasing oxidative phosphorylation. The STS-dependent increase in both Complex I and Complex II-dependent O(2) consumption was associated with increased oxidative stress and reduced ATP synthesis... These findings indicate that the glucose and amino acid deficiency conditions imposed by STS promote an anti-Warburg effect characterized by increased oxygen consumption but failure to generate ATP, resulting in oxidative damage and apoptosis." (abstract, results, passage verified)
    pubmedfull study (doi)
0:10:02Rhonda Patrick (host)supportedhigh

Cancer is the second leading cause of death in the United States.

"I know that um it's the second leading cause of death in the United States" (said at 0:10:02)

CDC National Vital Statistics System data confirm that cancer is the second leading cause of death in the United States, following heart disease.

0:09:50Rhonda Patrick (host)supportedmoderate

A study of Japanese centenarians, semi-supercentenarians, and supercentenarians found that low inflammation was the single biomarker consistently predictive of vitality, cognitive function, and mortality across all elderly age cohorts.

"they were looking at a variety of different biomarkers in uh the elderly population, in centenarians, in semi-supercentenarians, and in supercentenarians... And what was identified was the only biomarker that was consistent with all the age groups was um inflammation. So lower inflammation was predictive of vitality um and cognitive function, and it was considered to be the only thing that was driving the aging process or that could predict mortality aside from age itself." (said at 0:09:50)

A prospective study by Arai and colleagues (2015) evaluated 1,554 Japanese participants across community-based cohorts including very old individuals (85-99 years), centenarians, semi-supercentenarians, and supercentenarians, analyzing biomarker domains including inflammation, haematopoiesis, lipid and glucose metabolism, liver and renal function, and cellular senescence/telomere length. The study found that inflammation was the primary biomarker domain that consistently predicted all-cause mortality, physical capability, and cognitive function across the age cohorts, outperforming chronologic age and other biomarker domains.

0:20:22Valter Longosupportedmoderate

Under starvation conditions, normal cells enter a protected mode resistant to chemotherapy toxins, whereas cancer cells carrying oncogenes fail to activate this protective response (differential stress resistance).

"So you starve them, the normal cells go into the protective mode. When you starve a cancer cell, though, because the oncogenes um are the regulatory genes of this protection, a cancer cell by definition can never respond, right? So they're just—normal cells respond no matter what normal cell it is, from a a muscle cell to a hepatocyte to a brain cell. And uh but the cancer cells don't respond. Um and that's really the what's called differential stress resistance." (said at 0:20:22)

The speaker accurately defines the biological principle of differential stress resistance (DSR) described in preclinical oncology research. In response to nutrient deprivation or fasting, normal cells downregulate growth signaling pathways (such as IGF-1, RAS, and PKA) and divert energy toward cellular maintenance and stress-resistance mechanisms, shielding them from chemotherapy toxicity. In contrast, cancer cells harbor constitutively active oncogenes that prevent them from downregulating growth pathways and entering this protected state, leaving them susceptible to chemotherapeutic agents and oxidative damage.

0:31:28Valter Longosupportedmoderate

Fasting and fasting-mimicking diets increase cytotoxic T-lymphocytes and make cancer cells more exposed and vulnerable to the immune system by counteracting tumor immune-evasion mechanisms.

"Yeah, not just increase the number, which that's very much consistent with our older paper, but more so making the cancer cells exposed to it, right? So it's more about making the cancer cell more unable—like you were saying, normally the cancer cell figures out how to deal with the immune system and says, and has proteins that say, "I'm one of yours," right? And tricks the immune system in that sense. And so the fasting takes that away." (said at 0:31:28)

Preclinical and clinical trial evidence supports the claim that fasting and fasting-mimicking diets (FMD) enhance cytotoxic CD8+ T-cell infiltration and blunt tumor immune-evasion mechanisms. In mouse models of breast cancer and melanoma, FMD cycles combined with chemotherapy increased CD8+ tumor-infiltrating lymphocytes and downregulated tumor heme oxygenase-1 (HO-1), an enzyme that confers resistance to immune-mediated killing. In a clinical trial of 101 cancer patients, cyclic FMD reduced systemic immunosuppressive myeloid and regulatory T-cell subsets while promoting intratumoral cytotoxic/Th1 immune responses and interferon-gamma signatures.

  • supports: Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity. (Cancer cell 2016) · cited 394x in the literature
    "Here, we show that the combination of chemotherapy and a fasting-mimicking diet (FMD) increases the levels of bone marrow common lymphoid progenitor cells and cytotoxic CD8(+) tumor-infiltrating lymphocytes (TILs), leading to a major delay in breast cancer and melanoma progression. In breast tumors, this effect is partially mediated by the downregulation of the stress-responsive enzyme heme oxygenase-1 (HO-1). These data indicate that FMD cycles combined with chemotherapy can enhance T cell-dependent targeted killing of cancer cells both by stimulating the hematopoietic system and by enhancing CD8(+)-dependent tumor cytotoxicity." (abstract, results, passage verified)
    pubmedfull study (doi)
  • supports: Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients … (Cancer discovery 2022) · cited 312x in the literature
    "Integrated transcriptomic and deep-phenotyping analyses revealed that FMD profoundly reshapes anticancer immunity by inducing the contraction of peripheral blood immunosuppressive myeloid and regulatory T-cell compartments, paralleled by enhanced intratumor Th1/cytotoxic responses and an enrichment of IFNγ and other immune signatures associated with better clinical outcomes in patients with cancer." (abstract, results, passage verified)
    pubmedfull study (doi)
0:42:22Valter Longosupportedvery low

In a mouse model of multiple sclerosis, a fasting-mimicking diet destroyed autoimmune white blood cells, activated stem cells to generate non-autoimmune cells, decreased spinal cord inflammation, stimulated remyelination, and cured about 20% of the mice.

"in the mice, of course, we could demonstrate some things and these very clear effects, which was the fasting-mimicking diet causes the white blood cells, so the immune cells as I mentioned earlier, to be destroyed, partially destroyed, and then it turns on the stem cells. And when you make new cells, of course, they're no longer autoimmune, right? So the original cells are autoimmune—they're attacking the oligodendrocytes in the spinal cord. The new cells we've shown they're no longer autoimmune, and this leads to about 20% of the mice being disease-free, right? Meaning 20% of mice are cured from this autoimmunity, which is very much like multiple sclerosis. And the other thing that happens is that the oligodendrocytes—the inflammation goes down, right? Meaning the general inflammatory state around the spinal cord particularly goes down, and so this is very important because it allows the progenitor cells, so the ones that give rise to new myelin, so rebuild the spinal cord, they can now do their job and regenerate the system." (said at 0:42:22)

The speaker accurately describes the findings of a 2016 study published in Cell Reports (Choi et al., from Valter Longo's laboratory). In a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis, or EAE), periodic cycles of a fasting-mimicking diet reduced pro-inflammatory immune cells (TH1 and TH17 cells and antigen-presenting cells), promoted oligodendrocyte precursor cell regeneration and remyelination, reduced clinical severity across all treated mice, and completely reversed symptoms (disease-free/cured) in 20% of the animals. Because the primary findings describing this full mechanism and 20% complete reversal rate come from an animal model, the GRADE certainty is very low.

  • supports: A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Scler… (Cell reports 2016) · cited 514x in the literature
    "Here, we show that periodic 3-day cycles of a fasting mimicking diet (FMD) are effective in ameliorating demyelination and symptoms in a murine experimental autoimmune encephalomyelitis (EAE) model. The FMD reduced clinical severity in all mice and completely reversed symptoms in 20% of animals. These improvements were associated with increased corticosterone levels and regulatory T (Treg) cell numbers and reduced levels of pro-inflammatory cytokines, TH1 and TH17 cells, and antigen-presenting cells (APCs). Moreover, the FMD promoted oligodendrocyte precursor cell regeneration and remyelination in axons in both EAE and cuprizone MS models, supporting its effects on both suppression of autoimmunity and remyelination." (abstract, passage verified)
    pubmedfull study (doi)
0:54:08Rhonda Patrick (host)supportedmoderate

Eric Verdin's research showed that beta-hydroxybutyrate acts as an endogenous class I histone deacetylase (HDAC) inhibitor.

"Not to mention that, like, you know, beta-hydroxybutyrate has been identified to be a signaling molecule as well. I think Eric Verdin's work at UCSF showed it's a class I histone deacetylase inhibitor." (said at 0:54:08)

Eric Verdin's laboratory (Shimazu et al., Science 2013) demonstrated that the ketone body d-beta-hydroxybutyrate acts as an endogenous and specific inhibitor of class I histone deacetylases (HDACs). In cellular and mouse models, administration of beta-hydroxybutyrate or physiological states of fasting/calorie restriction led to increased histone acetylation and downstream activation of oxidative stress resistance genes.

0:56:01Valter Longosupportedvery low

Guido Kroemer demonstrated that autophagy induced during starvation or by caloric restriction mimetics is essential for exposing cancer cells to the immune system.

"I think this was in in the paper that was published together with ours by Guido Kroemer, and he showed, and Frank Madeo has also been doing work on that, but Guido was showing that autophagy was very, very important during the starvation or using starvation-mimicking drugs in causing the exposure of cancer cells to the immune system, right?" (said at 0:56:01)

The speaker accurately describes preclinical findings published by Guido Kroemer and colleagues (e.g., Pietrocola et al., Cancer Cell 2016). In mouse cancer models, short-term fasting and caloric restriction mimetics (such as hydroxycitrate and spermidine) triggered autophagy and enhanced anticancer immunosurveillance by depleting immunosuppressive regulatory T cells from the tumor bed. These therapeutic effects were observed exclusively in autophagy-competent tumors and required T lymphocytes. Because the direct causal demonstration of this mechanism comes from animal and cell models, the GRADE certainty for human clinical application is very low.

  • supports: Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance. (Cancer cell 2016) · cited 545x in the literature
    "Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed." (abstract, passage verified)
    pubmedfull study (doi)
0:58:30Valter Longosupportedmoderate

Resveratrol and spermidine function as fasting-mimicking compounds that activate cellular signaling pathways similar to fasting.

"for example, resveratrol, spermidine are considered fasting-mimicking drugs. Um they you know, they may not have the power of fasting, but certainly they push the cells in that direction. They they activate certain signaling pathways similar that are similar to fasting." (said at 0:58:30)

Resveratrol and spermidine are widely classified in the scientific literature as caloric restriction mimetics (CRMs) or fasting-mimicking compounds. Both compounds activate molecular signaling cascades that closely mirror those induced by nutrient deprivation and fasting, specifically promoting autophagy and protein deacetylation (e.g., via SIRT1 activation by resveratrol and EP300 acetyltransferase inhibition by spermidine). While extensive preclinical and mechanistic studies demonstrate these shared pathways, human clinical trials assessing their long-term healthspan benefits compared to actual fasting remain an active area of investigation.

  • supports: Caloric restriction mimetics: natural/physiological pharmacological autophagy inducers. (Autophagy 2014) · cited 104x in the literature
    "There are several examples of rather nontoxic natural compounds that act as AcCoA depleting agents (e.g., hydroxycitrate), acetyltransferase inhibitors (e.g., anacardic acid, curcumin, epigallocatechin-3-gallate, garcinol, spermidine) or deacetylase activators (e.g., nicotinamide, resveratrol), and that are highly efficient inducers of autophagy in vitro and in vivo, in rodents... Here, we speculate that CRM may mediate their broad health-improving effects by triggering the same molecular pathways that usually are elicited by long-term caloric restriction or short-term starvation and that imply the induction of autophagy as an obligatory event conferring organismal, organ- or cytoprotection." (abstract, passage verified)
    pubmedfull study (doi)
  • supports: Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Ther… (Cell metabolism 2019) · cited 630x in the literature
    "We define CRMs as compounds that ignite the protective pathways of caloric restriction by promoting autophagy, a cytoplasmic recycling mechanism, via a reduction in protein acetylation. Here, we describe the current knowledge on molecular, cellular, and organismal effects of known and putative CRMs in mice and humans." (abstract, passage verified)
    pubmedfull study (doi)
  • supports: Caloric Restriction Mimetics in Nutrition and Clinical Trials. (Frontiers in nutrition 2021) · cited 109x in the literature
    "Importantly, many of the CRM candidates activate autophagy, prolong life- and healthspan in model organisms and ameliorate diverse disease symptoms without the need to cut calories. Among others, glycolytic inhibitors (e.g., D-allulose, D-glucosamine), hydroxycitric acid, NAD + precursors, polyamines (e.g., spermidine), polyphenols (e.g., resveratrol, dimethoxychalcones, curcumin, EGCG, quercetin) and salicylic acid qualify as CRM candidates, which are naturally available via foods and beverages." (abstract, passage verified)
    pubmedfull study (doi)
1:00:36Valter Longosupportedmoderate

Nir Barzilai and colleagues are engaged in discussions with the FDA regarding advancing metformin as an anti-aging therapeutic candidate.

"And, for example, this is why metformin now is starting to very slowly move into the candidate position for an anti-aging drug. You know, Nir Barzilai and others are are talking to the FDA about moving forward with it because there's so much observation." (said at 1:00:36)

Dr. Nir Barzilai and collaborators have actively led the development of the Targeting Aging with Metformin (TAME) trial and engaged with regulatory authorities, including the FDA, to establish a framework for testing whether metformin can delay the onset of multiple age-related chronic diseases and multimorbidity in humans.

0:49:33Valter Longosupportedvery low

Research by David Sabatini and colleagues at MIT demonstrated that fatty acid metabolism plays a key role in the self-renewal and activation of intestinal stem cells.

"And this is the work by David Sabatini and others at MIT, and they're doing work on the fat and the role of fat and fatty acids, etc., on self-renewal and on the activation of stem cells, particularly in the gut." (said at 0:49:33)

Preclinical research from David Sabatini and Omer Yilmaz's laboratories at MIT and the Whitehead Institute demonstrated that fatty acid metabolism—specifically fatty acid oxidation (FAO) and PPAR-delta signaling—plays a critical role in the self-renewal, maintenance, and activation of intestinal stem cells (ISCs). In mouse models and ex vivo organoids, acute fasting augmented ISC function through induction of an FAO program, while genetic deletion of the rate-limiting enzyme Cpt1a abrogated these pro-regenerative effects and decreased ISC numbers. Additionally, treatment with fatty acid constituents enhanced the self-renewal capacity of intestinal organoids. Because the evidence is derived exclusively from animal and in vitro models, the certainty of evidence is very low.

0:48:33Rhonda Patrick (host)supportedmoderate

Quiescent hematopoietic stem cells rely primarily on glycolysis for energy metabolism, but switch to oxidative phosphorylation when they exit quiescence to self-renew or differentiate.

"at least with the hematopoietic cells—like, I'm not sure about with other stem cells and other tissues, but I know that when they're quiescent, when they're not dividing, they are glycolytic, meaning they use glucose for energy because they don't want to damage themselves with reactive oxygen species being generated as a byproduct of mitochondrial function, right? But I do know that when they come out of quiescence and they come out to either self-renew or differentiate into progenitor cells, oxidative phosphorylation becomes their source of making energy." (said at 0:48:33)

The host's statement accurately reflects established principles of hematopoietic stem cell (HSC) bioenergetics. Quiescent HSCs residing in the bone marrow microenvironment rely primarily on glycolysis for energy production, which helps limit mitochondrial oxidative stress and reactive oxygen species (ROS) generation to protect cellular integrity and maintain stemness. Upon exiting quiescence to activate, self-renew, or differentiate, HSCs undergo a metabolic shift toward mitochondrial oxidative phosphorylation to meet higher energy demands.

0:55:10Rhonda Patrick (host)supportedhigh

Chloroquine functions as an autophagy inhibitor and has been utilized in cancer therapeutics.

"I know that there's a very well-known inhibitor of autophagy called chloroquine, which is used to kill cancer." (said at 0:55:10)

Chloroquine and its derivative hydroxychloroquine are classic, well-established pharmacological inhibitors of autophagy that impair autophagic flux by preventing lysosomal acidification and autophagosome-lysosome fusion. Both compounds have been extensively investigated and utilized in preclinical studies and human clinical trials (typically as adjuvants combined with chemotherapy or radiotherapy) to sensitize and kill cancer cells.

1:02:45Valter Longosupportedvery low

Rapamycin administration has been associated with adverse effects including hyperglycemia, testicular degeneration, and cataracts.

"and you started seeing first all the positive results with rapamycin until, of course, you start getting the negative, right? And and it was hyperglycemia, testicular degeneration, cataracts, and these are probably just some." (said at 1:02:45)

Preclinical studies evaluating chronic rapamycin administration in mice have demonstrated these specific adverse effects alongside its lifespan-extending properties. In studies by the National Institute on Aging Interventions Testing Program and associated longevity trials, mice treated chronically with rapamycin exhibited a significantly increased incidence of testicular degeneration and cataracts, as well as impaired glucose homeostasis and insulin resistance. Because these findings are established primarily in animal models and clinical transplant contexts with high/chronic dosing, the evidence certainty is graded as very low.

  • supports: Rapamycin slows aging in mice. (Aging cell 2012) · cited 693x in the literature
    "We also note, however, that mice treated with rapamycin starting at 9 months of age have significantly higher incidence of testicular degeneration and cataracts; harmful effects of this kind will guide further studies on timing, dosage, and tissue-specific actions of rapamycin relevant to the development of clinically useful inhibitors of TOR action." (abstract, results, passage verified)
    pubmedfull study (doi)
1:04:50Valter Longosupportedvery low

Knocking out the growth hormone receptor in mice extends lifespan by 40% to 50% and approximately half reach old age with no observable diseases.

"So if you take a mouse and you knock out the growth hormone receptor, this mouse will live 40% 50% longer. It's also, in spite—and this is work by John Kopchick and Andrzej Bartke—and in spite of living longer, um it it has much less diseases. So almost half of these mice will get to the end of life with no diseases that are visible, right?" (said at 1:04:50)

Published work from the research groups of John Kopchick and Andrzej Bartke demonstrated that global disruption (knockout) of the growth hormone receptor/binding protein gene (GHR/BP-KO) in mice significantly extends lifespan (typically ~38% to 55%, depending on sex and strain) and delays age-related pathology. Subsequent end-of-life pathological assessments (e.g., Ikeno et al., 2009) confirmed that GHR-KO mice have a markedly reduced incidence and delayed occurrence of fatal neoplastic and non-neoplastic diseases, with a substantial fraction of long-lived knockout mice dying without evidence of overt fatal lesions. Because these data derive strictly from animal models, certainty is graded as very low.

1:05:15Valter Longosupportedmoderate

Humans in Ecuador with growth hormone receptor mutations almost never develop cancer or diabetes despite poor lifestyle factors.

"our work with humans that have the same mutation in the growth hormone receptor, and these people will live maybe a little bit longer, not not 40% longer for sure, um but they they have a terrible diet. They smoke, they drink, they really don't watch anything they do, and um and in spite of all this, um they never get almost never get cancer, they almost never get diabetes." (said at 1:05:15)

A 22-year longitudinal study of an Ecuadorian cohort with growth hormone receptor (GHR) deficiency (Laron syndrome) led by Guevara-Aguirre and Longo found that individuals carrying the GHR gene mutation exhibited near-total protection against cancer and diabetes compared to their unaffected relatives living in the same environment and socioeconomic conditions. Among the GHR-deficient cohort, researchers documented only one non-lethal cancer case and zero cases of diabetes, compared to a 17% cancer prevalence and 5% diabetes prevalence among unaffected control relatives.

1:06:08Rhonda Patrick (host)supportedhigh

Genetic polymorphisms in the IGF-1 receptor and FOXO genes are associated with human longevity.

"There's also human uh data showing that there's polymorphisms in, for example, the IGF-1 receptor uh or that whole pathway, you know, that are also consistent with longevity as well, right? GUEST1: Yeah, FOXO that uh FOXO in the IGF-1 receptor, in the growth hormone receptor. So it's all consistent, right, I think." (said at 1:06:08)

Human genetic association studies and meta-analyses confirm that genetic polymorphisms in the insulin-like growth factor-1 receptor (IGF-1R), FOXO genes (specifically FOXO3A), and the growth hormone receptor (GHR)—all central to the growth hormone/IGF-1 signaling axis—are associated with human longevity. A 2014 systematic review and meta-analysis confirmed significant associations between longevity and specific polymorphisms in both IGF-1R (rs2229765) and FOXO3A (rs2764264, rs2802292, rs9400239, rs479744). Furthermore, cohort studies in centenarians have identified functional mutations in IGF1R and specific variants in GHR (such as the d3-GHR exon 3 deletion) that are significantly enriched in long-lived individuals.

1:06:26Rhonda Patrick (host)supportedvery low

Inhibiting the IGF-1 signaling pathway in C. elegans worms increases their lifespan by 100%.

"manipulating the IGF-1 signaling pathway in worms uh in Andrew Dillin's lab at the Salk Institute. And I remember when I saw, you know, when you get rid of that pathway um and in these worms they live 100% longer" (said at 1:06:26)

In Caenorhabditis elegans, genetic downregulation or inhibition of the insulin/IGF-1 receptor pathway (principally via mutations in the daf-2 gene, an insulin/IGF-1 receptor homolog) is well-documented to double adult lifespan (~100% increase) in a DAF-16/FOXO-dependent manner. Because this finding is based entirely on invertebrate model organism studies, the certainty of evidence for broader physiological translation is rated very low.

1:08:45Valter Longosupportedvery low

In immune-deficient mice, cancer tumors grow significantly faster.

"we know that if you if you have a immune-deficient mouse, the cancer grows a lot faster." (said at 1:08:45)

Preclinical animal models demonstrate that an intact immune system exerts continuous immunosurveillance and restrains tumor development and progression. In immunodeficient mice (such as those lacking Rag2, IFN-γ signaling, or functional T cells), both transplanted and carcinogen-induced tumors proliferate without immune-mediated elimination or equilibrium, leading to accelerated tumor growth and earlier onset of clinically detectable tumors compared to immunocompetent controls. Because the available evidence consists of laboratory animal experiments, certainty is graded as very low.

1:11:25Rhonda Patrick (host)supportedvery low

Exercise causes circulating IGF-1 to cross the blood-brain barrier into the brain in mice.

"because in mice it's been shown that that exercise causes IGF-1 um to cross the blood-brain barrier and get into the brain." (said at 1:11:25)

Animal research in rodents demonstrates that exercise stimulates the uptake and transport of circulating, blood-borne insulin-like growth factor 1 (IGF-1) across the blood-brain and blood-cerebrospinal fluid interfaces into specific brain regions (such as the hippocampus), mediating exercise-induced neurogenesis and neuroprotection. Because the supporting evidence comes exclusively from animal studies, certainty is very low.

1:13:05Valter Longosupportedmoderate

Clinical evaluation of the fasting-mimicking diet shows significant reduction in visceral fat while preserving lean body mass.

"clinically, we see a specific loss of of fat only significant in the visceral area, and then no loss or very minimal loss of lean body mass, right? Because it There is temporary loss, but then rebuild, right?" (said at 1:13:05)

Randomized clinical trials evaluating periodic cycles of the fasting-mimicking diet (FMD, 5 days per month over 3 to 4 months) show significant reductions in total body fat, trunk/visceral fat, and hepatic fat, while preserving lean body mass (fat-free mass) compared to continuous dietary interventions or standard diets.

1:09:50Rhonda Patrick (host)supportedmoderate

IGF-1 and brain-derived neurotrophic factor (BDNF) cross or act across the blood-brain barrier to promote the growth of new brain cells.

"IGF-1 plays an important role in muscle growth, muscle repair, and also it crosses the blood-brain barrier and plays an important role, along with brain-derived neurotrophic factor, for growing new brain cells." (said at 1:09:50)

Preclinical and mechanistic evidence supports the claim. Circulating insulin-like growth factor 1 (IGF-1) crosses the blood-brain barrier into brain regions including the hippocampus. In rodent models, uptake of circulating IGF-1 is required for exercise-induced increases in adult hippocampal neurogenesis (the generation of new neurons), where it acts in coordination with brain-derived neurotrophic factor (BDNF) and downstream signaling cascades to stimulate neural stem cell proliferation and neuronal survival.

  • supports: Circulating insulin-like growth factor I mediates exercise-induced increases in the number… (The Journal of neuroscience : the official journal of the Society for Neuroscience 2001) · cited 1022x in the literature
    "exercise stimulates uptake of the neurotrophic factor insulin-like growth factor I (IGF-I) from the bloodstream into specific brain areas, including the hippocampus. In addition, IGF-I participates in the effects of exercise on hippocampal c-fos expression and mimics several other effects of exercise on brain function. Because subcutaneous administration of IGF-I to sedentary adult rats markedly increases the number of new neurons in the hippocampus, we hypothesized that exercise-induced brain uptake of blood-borne IGF-I could mediate the stimulatory effects of exercise on the adult hippocampus. Thus, we blocked the entrance of circulating IGF-I into the brain by subcutaneous infusion of a blocking IGF-I antiserum to rats undergoing exercise training. The resulting inhibition of brain uptake of IGF-I was paralleled by complete inhibition of exercise-induced increases in the number of new neurons in the hippocampus." (abstract, passage verified)
    pubmedfull study (doi)
  • supports: Cellular and Molecular Regulation of Exercise-A Neuronal Perspective. (Cellular and molecular neurobiology 2023) · cited 40x in the literature
    "Exerkines such as FNDC5/irisin, Cathepsin B, Adiponectin, and IL-6 circulate through the bloodstream, cross the blood-brain barrier, and modulate the expression of important signaling molecules such as AMPK, SIRT1, PGC1α, BDNF, IGF-1, and VEGF which further contribute to improved energy metabolism, glucose homeostasis, insulin sensitivity, neurogenesis, synaptic plasticity, and overall well-being of the body and brain." (abstract, passage verified)
    pubmedfull study (doi)
3

No source found (not proven false)

0:18:18Valter Longounverifiedvery low

Cancer is the leading cause of death in many European countries.

"In Europe it's the same way. In a lot of places it's number one." (said at 0:18:18)

No published record matching the claim that cancer is the leading cause of death in many European countries was located; this does not prove the claim false.

0:13:16Valter Longounverifiedvery low

Initiating a fasting-mimicking diet in middle-aged mice significantly reduces systemic inflammation.

"I mean we show a decrease in inflammation in the mice that were given the fasting-mimicking diet started at middle age" (said at 0:13:16)

No published record matching the claim that initiating a fasting-mimicking diet in middle-aged mice significantly reduces systemic inflammation was located; this does not prove the claim false.

0:44:56Valter Longounverifiedvery low

In a clinical trial led by Markus Bock, a single seven-day cycle of a fasting-mimicking diet followed by a Mediterranean diet produced better outcomes in multiple sclerosis patients than six months of a continuous ketogenic diet.

"And this is Markus Bock in Berlin that was the lead person in the study. But I mean, the amazing thing is that a week of fasting followed by Mediterranean diet, which is really a regular diet, did better than six months of ketogenic diet, right? ... So it was one week of fasting-mimicking diet—one single time, seven days, and then the rest of the six months a regular Mediterranean diet." (said at 0:44:56)

No published record matching the claim that a single seven-day cycle of a fasting-mimicking diet followed by a Mediterranean diet produced better outcomes in multiple sclerosis patients than six months of a continuous ketogenic diet was located; this does not prove the claim false.

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.