HoldsUp

FoundMyFitness · 2016-03-14 · Rhonda Patrick (host), Peter Attia

Peter Attia, M.D. on Macronutrient Thresholds for Longevity and Performance, Cancer and More

43 claims checked against research: 4 contradicted 3 overstated 6 needing context 29 supported 1 unverified

6

Needs context

0:04:48Peter Attianeeds contextvery low

Absence of mTORC1 in skeletal muscle causes muscle withering and wasting.

"So if you have no mTORC1, for example, in your muscles, you'd wither away and that would be a debilitating condition." (said at 0:04:48)

Preclinical animal models confirm that genetic ablation of essential mTORC1 components (such as Raptor) during skeletal muscle development and growth causes progressive muscular dystrophy, severe myopathy, and premature death. However, inducible deletion of mTORC1 signalling specifically in fully mature, sedentary adult mouse muscle does not immediately cause severe muscle wasting over several months, although it does impair muscle contractility, neuromuscular integrity, and translation machinery. Evidence is limited to animal knockout models.

0:07:30Peter Attianeeds contextmoderate

mTORC1 in muscle tissue has a significantly higher affinity for leucine than mTORC1 in adipose tissue or hepatocytes.

"mTORC1 in muscle has a much higher affinity for leucine than mTORC1 in fat or in hepatocytes." (said at 0:07:30)

mTORC1 itself does not directly bind leucine; rather, intracellular leucine is sensed upstream by the Sestrin family of proteins (Sestrin1, Sestrin2, and Sestrin3), which regulate mTORC1 via the GATOR2-GATOR1-Rag GTPase pathway. Skeletal muscle predominantly expresses Sestrin1, which exhibits the highest binding affinity for leucine among the Sestrin isoforms, whereas other tissues such as the liver or adipose tissue rely on different isoform distributions (e.g., Sestrin2). Thus, while the underlying leucine-sensing machinery upstream of mTORC1 confers distinct tissue-specific sensitivity and affinity to leucine in skeletal muscle, the phrasing refers to upstream leucine sensors rather than the mTORC1 complex directly.

0:15:29Peter Attianeeds contexthigh

Cardiovascular and cerebrovascular disease, cancer, and neurodegenerative disease together account for approximately 75% of deaths.

"if you want to live longer, the name of the game is delaying the onset of the big three—the big three being the diseases that will kill 75% of us: cerebrovascular and cardiovascular, cancer, and neurodegenerative." (said at 0:15:29)

According to the Global Burden of Disease (GBD) Study and national vital statistics, all non-communicable diseases (NCDs) combined account for approximately 73.4% of all global deaths. Cardiovascular and cerebrovascular diseases (the leading cause of death globally and in developed countries) and neoplasms (cancer, the second leading cause) together account for roughly 45% to 50% of global mortality, while neurodegenerative disorders (such as Alzheimer's disease and other dementias) account for approximately 4% to 7% (higher in aging, high-income populations). While cardiovascular disease, cancer, and neurodegenerative diseases represent the vast majority of chronic adult mortality, reaching the ~75% threshold encompasses the broader category of all non-communicable diseases, which also includes chronic respiratory diseases, diabetes, and kidney diseases.

0:37:32Rhonda Patrick (host)needs contextvery low

Research from the Gladstone Institutes shows APOE4 exhibits a dominant negative effect where the protein is cleaved and forms aggregates that activate microglia and trigger an inflammatory cascade in the brain.

"research—a lot of it coming out of UCSF Gladstone Institute—showing that in addition to a loss of function with APOE4, there's also a dominant negative effect. So apparently the APOE4, there's this two-amino-acid, you know, substitution, and structurally, if you look at the the structure of the protein, um, it starts to get cleaved. And so it itself starts to accumulate these like aggregates that it then, you know, keep you get more activated microglia and it keeps like spiraling out this whole inflammatory process in the brain." (said at 0:37:32)

Research from the Gladstone Institutes (e.g., Mahley, Huang, and colleagues) established that APOE4 undergoes neuron-specific proteolytic cleavage more readily than APOE3, generating C-terminal truncated fragments that exert a toxic gain-of-function effect in Alzheimer's disease models. However, the mechanism identified by Gladstone researchers involves these fragments entering the neuronal cytosol to disrupt the cytoskeleton, induce tau hyperphosphorylation, and cause direct neurotoxicity, rather than forming extracellular aggregates that drive microglial activation and neuroinflammation as described by the host. Additionally, the evidence for this proteolytic cleavage mechanism comes primarily from transgenic mouse models and in vitro systems.

0:46:43Peter Attianeeds contexthigh

Amgen conducted a Phase 2 trial of an IGF receptor antibody in advanced pancreatic cancer that failed despite reducing IGF levels at the receptor by 50%, and the antibody does not cross the blood-brain barrier.

"Amgen had a drug that was an IGF receptor antibody. It went into clinical trials, Phase 2 trials, in pancreatic cancer, advanced pancreatic cancer, and it failed. Now, it failed despite reducing IGF levels at the receptor by 50%. ... What's most interesting is that antibody does not cross the blood-brain barrier." (said at 0:46:43)

Amgen developed ganitumab (AMG 479), a monoclonal antibody targeting the insulin-like growth factor 1 receptor (IGF-1R), for advanced pancreatic cancer. However, the claim needs qualification: the randomized Phase 2 trial showed promising trends toward improved survival, leading to a large Phase 3 trial (the GAMMA trial), which ultimately failed to improve overall survival (median 7.0 vs 7.2 months). Additionally, while full-length monoclonal antibodies generally do not cross the blood-brain barrier, pancreatic adenocarcinoma is an abdominal tumor, making blood-brain barrier penetration irrelevant to the drug's therapeutic efficacy or failure in pancreatic cancer.

0:48:20Rhonda Patrick (host)needs contextmoderate

Astrocytes in the brain are glycolytic and metabolize glucose into lactate, which is then shuttled into neurons for mitochondrial energy metabolism.

"What's really interesting to me is the fact that neurons are actually mostly using lactate from astrocytes. Astrocytes are glycolytic, so the astrocytes are supporting cells in your brain, which are using glucose mostly. Are what using glucose to generate lactate. Lactate then gets shuttled into neurons, and then the neurons And the reason why neurons like that is because it's thermodynamically favorable" (said at 0:48:20)

The speaker is describing the Astrocyte-Neuron Lactate Shuttle (ANLS) hypothesis, first proposed by Pellerin and Magistretti. Under this model, astrocytes exhibit a predominantly glycolytic phenotype, metabolizing glucose or glycogen into lactate, which is then transported via monocarboxylate transporters into oxidative neurons to fuel mitochondrial metabolism. While extensively supported in biochemical, cell culture, and animal models, stating as an absolute fact that neurons 'mostly' rely on astrocyte-derived lactate overstates a debated model in neuroenergetics: substantial direct glucose uptake and oxidation by neurons also occur, and the quantitative dominance of lactate shuttling under resting versus activated conditions remains an active topic of research.

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.