HoldsUp

FoundMyFitness · 2023-12-27 · Rhonda Patrick (host), Peter Attia

Dr. Peter Attia on Mastering Longevity – Insights on Cancer Prevention, Heart Disease, and Aging

135 research-tied claims examined: 13 contradicted 8 overstated 16 context 83 supported 15 unverified

16

Needs context

0:28:28Rhonda Patrick (host)needs contextmoderate

Very-low-density lipoproteins (VLDL) transport inflammatory proteins such as cytokines and C-reactive protein.

"It's also transporting—and this is where I was so intrigued—inflammatory proteins. So cytokines, C-reactive protein also are being transported through VLDL." (said at 0:28:28)

C-reactive protein (CRP) can bind directly to very-low-density lipoproteins (VLDL) through interactions with surface phosphocholine and apolipoprotein B (ApoB). Early purification studies frequently co-isolated CRP with VLDL because of these physical binding affinities. However, characterizing VLDL as a primary circulating transport vehicle for inflammatory proteins like CRP and cytokines requires qualification: while lipoproteins interact with and bind inflammatory mediators (such as CRP binding to ApoB-containing lipoproteins under specific structural conditions), CRP primarily circulates as a soluble plasma protein synthesized by the liver, rather than being fundamentally packaged into VLDL for systemic transport.

0:30:36Peter Attianeeds contextmoderate

In humans, LDL performs the majority of reverse cholesterol transport by receiving cholesterol transferred from HDLs and transporting it back to the liver.

"I mean, in us, LDL is doing the majority of what's called reverse cholesterol transport, so RCT, which is kind of like the good movement of cholesterol... And LDL is doing the majority of that. So HDLs are typically transferring their cholesterol to LDLs, and LDLs are bringing them back to the liver." (said at 0:30:36)

In species expressing cholesteryl ester transfer protein (CETP) such as humans, reverse cholesterol transport (RCT) occurs via two distinct routes: the direct pathway, where HDL delivers cholesteryl esters directly to the liver via scavenger receptor class B type I (SR-BI), and the indirect pathway, where CETP transfers cholesteryl esters from HDL to apolipoprotein B-containing lipoproteins (VLDL, IDL, and LDL) for hepatic clearance via the LDL receptor. In humans, the indirect CETP-mediated pathway constitutes a major route of plasma cholesteryl ester clearance back to the liver. However, RCT is fundamentally an integrated multi-step system initiated by HDL-mediated cellular cholesterol efflux from peripheral tissues, rather than LDL acting independently.

0:32:28Peter Attianeeds contextmoderate

Human infants are typically born with an LDL cholesterol or ApoB level below 20 mg/dL.

"So if you look at a child, they're born with an LDL cholesterol or ApoB level typically below 20 milligrams per deciliter." (said at 0:32:28)

At birth, circulating levels of low-density lipoprotein (LDL) cholesterol and apolipoprotein B (ApoB) in umbilical cord blood are markedly lower than in older children and adults, typically averaging around 25 to 35 mg/dL (~0.7–0.9 mmol/L) for LDL cholesterol and approximately 20 to 30 mg/dL for ApoB. While physiological levels at birth are indeed very low compared to adult reference ranges and increase substantially over the first months of life, stating that they are typically below 20 mg/dL understates typical neonatal average concentrations.

0:36:55Peter Attianeeds contexthigh

Globally, ASCVD kills approximately 19 million people annually compared to 12 or 13 million for cancer.

"In fact, when you talk about it globally, the gap between ASCVD and cancer is even bigger: it's like 19 million people annually to 12 or 13 million for cancer." (said at 0:36:55)

Global epidemiological data roughly align with the comparison, though the mortality gap between cardiovascular disease and cancer is even wider than stated. According to Global Burden of Disease estimates, total cardiovascular diseases (primarily driven by atherosclerotic conditions such as ischemic heart disease and ischemic stroke) account for approximately 18 to 20 million deaths annually (around 19 million). Global cancer mortality, as documented by the International Agency for Research on Cancer (GLOBOCAN), was estimated at approximately 9.7 million deaths in 2022 and 10.0 million deaths in 2020 (with newly diagnosed cancer cases totaling approximately 19 to 20 million annually). While cardiovascular disease is indeed the leading global cause of death, cancer mortality is around 10 million rather than 12 to 13 million.

0:53:33Peter Attianeeds contextmoderate

Triparanol, approved in the 1950s/1960s to lower cholesterol, worked by inhibiting the enzyme converting desmosterol to cholesterol, which caused desmosterol accumulation and increased heart attacks.

"So the very first, uh, drug that was ever used to lower lipids, uh, was a was a drug called, uh, oh God, I'm always blanking on the name of this, like, uh, triparanol... it turned out this drug lowered cholesterol by inhibiting an enzyme that was the final enzyme in this step that we use to make cholesterol... one of the pathways, uh, results in a molecule called desmosterol, which gets converted into cholesterol. So there's an enzyme that facilitates that, and this drug blocked that enzyme... but it was found that the patients on this drug, even though they had lower cholesterol, had a higher incidence of heart attacks." (said at 0:53:33)

The claim is partially accurate regarding triparanol's mechanism of action, but inaccurate regarding the primary reason for its withdrawal and the clinical outcomes reported. Approved in 1960 under the trade name MER-29, triparanol was indeed one of the first synthetic cholesterol-lowering drugs used clinically. It inhibited 24-dehydrocholesterol reductase (DHCR24), the enzyme that converts desmosterol to cholesterol, leading to an accumulation of desmosterol in plasma and tissues. However, triparanol was withdrawn from the market in 1962 primarily due to severe toxicities including cataracts, alopecia (hair loss), ichthyosis (skin disorders), and adrenal insufficiency, rather than a demonstrated increase in heart attacks in clinical trials.

0:57:56Peter Attianeeds contexthigh

Approximately 7% of patients on statins develop muscle aches as a side effect.

"Well, about 7% of people develop muscle aches on statins. So that's a If you think about how many people are on those drugs or how many people are prescribed those drugs, that's a huge number of people." (said at 0:57:56)

A 2022 meta-analysis of 176 studies covering over 4 million patients found that the prevalence of statin intolerance (which is primarily driven by muscle symptoms) is approximately 7.0% using National Lipid Association (NLA) criteria (6.7% by ILEP and 5.9% by EAS criteria). However, evidence from large-scale double-blind randomized trials indicates that the vast majority of muscle aches experienced while taking statins are not pharmacologically caused by the drug itself. A 2022 Cholesterol Treatment Trialists' Collaboration meta-analysis of 19 double-blind placebo-controlled trials (n=123,940) showed that 27.1% of patients allocated statins vs. 26.6% on placebo reported muscle pain or weakness. During the first year of therapy, statins produced a 7% relative increase in muscle symptoms (rate ratio 1.07), representing an absolute excess of only about 11 cases per 1,000 person-years (~1%), meaning over 90% of muscle symptoms reported during statin therapy are not caused by the statin.

  • supports: Prevalence of statin intolerance: a meta-analysis. (European heart journal 2022) · cited 468x in the literature
    "A total of 176 studies [112 randomized controlled trials (RCTs); 64 cohort studies] with 4 143 517 patients were ultimately included in the analysis. The overall prevalence of SI was 9.1% (95% confidence interval 8.0-10%). The prevalence was similar when defined using NLA, ILEP, and EAS criteria [7.0% (6.0-8.0%), 6.7% (5.0-8.0%), 5.9% (4.0-7.0%), respectively]." (abstract, results, passage verified)
    pubmedfull study (doi)
  • context: Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis … (Lancet (London, England) 2022) · cited 260x in the literature
    "Among 19 placebo-controlled trials... during a weighted average median follow-up of 4·3 years, 16 835 (27·1%) allocated statin versus 16 446 (26·6%) allocated placebo reported muscle pain or weakness (rate ratio [RR] 1·03; 95% CI 1·01-1·06). During year 1, statin therapy produced a 7% relative increase in muscle pain or weakness (1·07; 1·04-1·10), corresponding to an absolute excess rate of 11 (6-16) events per 1000 person-years, which indicates that only one in 15 ([1·07-1·00]/1·07) of these muscle-related reports by participants allocated to statin therapy were actually due to the statin." (abstract, results)
    pubmedfull study (doi)
1:43:52Peter Attianeeds contextmoderate

Elevated blood glucose levels cause protein glycosylation that occludes microvascular capillary beds and impairs tissue oxygen delivery.

"And so as the proteins in our blood get glycosylated and get stickier, one, their function is lower, but two, they also tend to obscure the narrowest part of our vascular system. So the tiniest, tiniest, tiniest capillaries become more occluded, and therefore it's harder to deliver oxygen to those tissues." (said at 1:43:52)

Hyperglycemia and the non-enzymatic glycation of proteins leading to advanced glycation end products (AGEs) play a central role in diabetic microvascular disease. This process induces extracellular matrix accumulation, basement membrane thickening, endothelial dysfunction, capillary narrowing/occlusion, and resulting tissue hypoxia. However, the speaker simplifies the mechanism: glycation leads to progressive microangiopathy and structural vessel wall changes over time rather than simple mechanical clogging of capillaries by sticky circulating proteins, and non-enzymatic glycation is distinct from physiological enzymatic glycosylation.

1:44:45Peter Attianeeds contextmoderate

Elevated glucose levels primarily damage small blood vessels while elevated insulin levels primarily damage large blood vessels.

"So as a general rule, elevated levels of glucose are damaging to small vessels; elevated levels of insulin are damaging to large blood vessels. So the eyes, the kidneys, the microvasculature of the heart and the brain are very susceptible to high levels of glucose. The larger blood vessels of the heart, the aorta, the iliac vessels, carotid arteries, more susceptible to the elevated levels of insulin." (said at 1:44:45)

The speaker's statement reflects a classic clinical heuristic: glycemic control predominantly demonstrates clear risk reduction for microvascular complications (such as diabetic retinopathy, nephropathy, and neuropathy), whereas hyperinsulinemia, insulin resistance, and associated cardiometabolic factors strongly drive macrovascular atherosclerotic disease (affecting large vessels like coronary, carotid, and peripheral arteries). However, presenting this as a strict division oversimplifies vascular pathophysiology. Published evidence shows that both chronic hyperglycemia and hyperinsulinemia/insulin resistance act concurrently across both vessel sizes: hyperglycemia contributes to large-vessel atherosclerosis through endothelial dysfunction, oxidative stress, and advanced glycation end products (AGEs), while insulin resistance and hyperinsulinemia impair microvascular endothelial function and capillary perfusion.

2:32:15Peter Attianeeds contexthigh

Lung cancer is the leading cause of cancer death globally and in the United States for both men and women, and 85% of lung cancers occur in current or former smokers.

"lung cancer is the leading cause of cancer death globally and in the US for both men and women, and 85% of lung cancers occur in former smokers or current smokers." (said at 2:32:15)

The statement is largely accurate but requires geographic qualification regarding sex-specific mortality. In the United States, lung cancer is indeed the leading cause of cancer death for both men and women, exceeding deaths from breast and prostate cancers. Globally, lung cancer is the leading cause of cancer death overall (accounting for approximately 18.7% of all cancer deaths) and the leading cause of cancer death in men; however, female breast cancer remains the leading cause of cancer death among women worldwide. Epidemiological data consistently confirm that approximately 80% to 85% of lung cancer cases occur in individuals with a history of tobacco smoking (current or former smokers).

2:34:20Peter Attianeeds contexthigh

Living at a 1-mile altitude like Denver doubles background radiation exposure compared to sea level.

"If you live in Denver, you're doubling that, so being one mile in the sky doubles your exposure, but you're still at 4 to 8% of your annual allotment." (said at 2:34:20)

The speaker states that living at a 1-mile altitude like Denver doubles radiation exposure compared to sea level, but accurately notes that it represents only a small fraction (4–8%) of regulatory/annual exposure limits. In reality, living at high elevation approximately doubles the *cosmic* component of natural background radiation—increasing cosmic radiation exposure from about 0.3 mSv/year (30 mrem/year) at sea level to roughly 0.5–0.6 mSv/year at Denver's altitude—rather than doubling total natural background radiation exposure. Total background radiation includes radon, terrestrial radioisotopes, and internal radionuclides (averaging ~2.4 mSv/year worldwide), of which cosmic radiation comprises only a fraction. As noted in assessments of natural radiation sources, cosmic radiation accounts for approximately 0.39 mSv out of a total average annual natural background exposure of 2.4 mSv (UNSCEAR data cited in research). Thus, while cosmic ray dose approximately doubles with elevation from sea level to Denver, total background radiation exposure increases by a much smaller percentage.

3:02:00Peter Attianeeds contexthigh

Ceasing estrogen replacement therapy results in a rapid decline in bone mineral density because estrogen is the primary transducing signal that couples mechanical bone loading to osteoblast and osteoclast activity.

"what is unambiguously clear is her bones are going to get brittle again, cuz the moment you take the estrogen away, bone density goes down. Estrogen is the most important hormone in men and women for the regulation of BMD. It is the chemical transduction system that turns force into bone building. So So we have, you know, basically strain gauges in our bones that are sensing forces on the bones, and that force is being turned via estrogen into a chemical signal to osteoblasts and osteoclasts to promote bone building." (said at 3:02:00)

The speaker's assertion bundles two distinct claims. First, the statement that discontinuing estrogen replacement therapy leads to rapid loss of bone mineral density (BMD) is well-supported by high-quality evidence. Systematic reviews of randomized controlled trials show rapid BMD declines of 2.3% to 6.2% within the first year of stopping hormone therapy. Second, describing estrogen as 'the chemical transduction system that turns force into bone building' requires qualification. In skeletal biology, osteocytes act as the primary mechanosensors ('strain gauges'), converting mechanical strain and fluid flow into biochemical signals through dedicated mechanosensitive structures—most notably Piezo1 ion channels, integrin cell-matrix adhesions, and primary cilia. Estrogen and estrogen receptor-alpha (ERα) interact with and augment these mechanotransduction pathways (such as integrin αvβ3, YAP/TAZ, and Wnt/β-catenin signaling), but estrogen itself is a regulatory hormone modulating osteocyte mechanosensitivity rather than the direct transducer of physical force.

3:03:25Peter Attianeeds contextmoderate

Bisphosphonates are clinically indicated for only 3 to 5 years of use.

"First of all, you only use bisphosphonates for 3 to 5 years." (said at 3:03:25)

While 3 to 5 years represents the standard duration of initial bisphosphonate therapy before clinical reassessment and consideration of a 'drug holiday' (typically 3 years for intravenous formulations and 5 years for oral formulations), it is not a strict upper limit for all patients. Clinical guidelines from organizations such as the American Society for Bone and Mineral Research (ASBMR) recommend that patients at persistent high risk of fracture (e.g., older adults, those with very low hip T-scores, or those with previous major osteoporotic fractures) continue bisphosphonate treatment for up to 6 to 10 years with periodic evaluation.

2:37:24Peter Attianeeds contextmoderate

Estradiol can be converted to estrone (E1) and estriol (E3), but estriol cannot be converted back to estradiol or estrone; estrone metabolizes into 2-, 4-, and 16-hydroxyestrone, whereas estriol can metabolize into 2-hydroxyestrone but not 4- or 16-hydroxyestrone.

"Estradiol can be turned into estrone, which is E1, and it can be turned into E3, estriol. But E3 cannot be turned into E2 or E1, so that's a one-way arrow. E1 can be turned into a 2-, 4-, and 16-hydroxyestrone. So you've got E1 can be turned into a 2-hydroxy, a 4-hydroxy, or a 16-hydroxy. E3 can actually be turned into the 2-hydroxy, but not the 4-hydroxy or the 16-hydroxy." (said at 2:37:24)

The speaker's outline of estrogen pathways is broadly accurate regarding conversion directions, but contains terminology imprecisions. In human estrogen metabolism, estradiol (E2) reversibly interconverts with estrone (E1), and E1/E2 can be metabolized down the 16α-pathway into 16α-hydroxyestrone and ultimately estriol (E3), a terminal conversion that does not convert back to E1 or E2. E1 is primarily hydroxylated into 2-hydroxyestrone, 4-hydroxyestrone, and 16α-hydroxyestrone. However, estriol is already 16α-hydroxylated (estratriene-3,16α,17β-triol); further A-ring metabolism of estriol yields 2-hydroxyestriol (a catechol estrogen), not 2-hydroxyestrone.

5:19:02Peter Attianeeds contexthigh

In a large clinical trial of high-risk men receiving testosterone, there was a slight increase in major adverse cardiovascular events (MACE) at 1 year post-initiation compared to placebo that was not present at 2 and 3 years.

"there's um a very large study that looked at kind of high-risk men, and they were given testosterone, and at one year post-initiation of TRT, there was a slight increase in the risk of major adverse cardiac events in the testosterone group compared to the placebo group that vanished at 2 and 3 years" (said at 5:19:02)

The speaker is referring to the TRAVERSE trial (Lincoff et al., 2023), a randomized, double-blind, placebo-controlled trial of 5,246 men aged 45 to 80 with hypogonadism and preexisting cardiovascular disease or high cardiovascular risk. Over a mean follow-up of 33 months, testosterone replacement therapy was noninferior to placebo for the primary major adverse cardiovascular event (MACE) composite end point (7.0% in the testosterone group vs. 7.3% in the placebo group; HR 0.96; 95% CI, 0.78 to 1.17). While time-to-event curves displayed a slight early excess of events in the testosterone group around the first year before converging and crossing the placebo curve at years 2 and 3, this early difference was minor, statistically non-significant, and the overall trial established cardiovascular safety/noninferiority.

5:19:45Peter Attianeeds contexthigh

The SPRINT trial demonstrated that maintaining blood pressure at 120/80 mmHg or lower provides superior cardiovascular outcomes compared to higher targets.

"if you look at the SPRINT trial, I think it's very clear that 120 over 80 or better is the place to be." (said at 5:19:45)

The SPRINT trial (Systolic Blood Pressure Intervention Trial) evaluated 9,361 adults at increased cardiovascular risk (excluding those with diabetes mellitus or previous stroke) randomized to an intensive systolic blood pressure (SBP) target of <120 mm Hg versus a standard target of <140 mm Hg. The trial found that intensive systolic BP targeting resulted in significantly lower rates of fatal and nonfatal major cardiovascular events (HR 0.75; 95% CI, 0.64 to 0.89) and all-cause mortality (HR 0.73; 95% CI, 0.60 to 0.90). However, SPRINT specifically targeted systolic blood pressure rather than a combined diastolic target of 80 mm Hg, and the findings apply specifically to high-risk non-diabetic populations while noting an increase in adverse events such as hypotension, syncope, electrolyte abnormalities, and acute kidney injury.

3:36:35Peter Attianeeds contexthigh

In the SPRINT trial blood pressure protocol, participants sat for 5 minutes without stimulation before having blood pressure measured, repeated for checks at 5, 10, and 15 minutes.

"Measuring blood pressure, yeah. So, um, this was established really clearly through the SPRINT trial, and and this has basically been now kind of the gold standard for how we use an automated cuff. So that trial was done by um having individuals sit for 5 minutes, check a blood pressure, no stimulation during that time, so not talking, not looking at a phone, not doing anything, and then repeat that two more times. So it's a 15—I'm not suggesting this is what Dan does or what anybody does, but just so you understand at the level of how the trials are done, you're sitting for 15 minutes, having a check at 5, 10, and 15 minutes." (said at 3:36:35)

In the SPRINT trial (and standard automated office blood pressure protocols), blood pressure was measured using an automated oscillometric device programmed for an initial 5-minute rest period without stimulation or observer presence, followed by three automated readings taken at 1-to-2-minute intervals (averaging all three readings). The entire measurement process took approximately 7 to 9 minutes, rather than requiring 5-minute rest intervals between each measurement (checks at 5, 10, and 15 minutes).

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.