Best of 2025: Heart Disease, Exercise & Longevity What the Evidence Shows | The Proof The Proof with Simon Hill

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Gemini Summary:

Here is the high-resolution summary and analysis of “Best of the Proof 2025 Part Two.”

Executive Summary

This compilation episode synthesizes expert perspectives on cardiovascular disease prevention, metabolic fitness, and nutrition science, challenging several pervading health myths. A central theme is the aggressive, early management of cardiovascular risk factors. Dr. Laurence Sperling and Dr. Thomas Dayspring argue that the “optimal” LDL cholesterol level for preventing atherosclerosis is far lower than standard guidelines suggest—ideally below 70 mg/dL or even 55 mg/dL. They emphasize that atherosclerosis is a cumulative, decades-long process; therefore, waiting for high 10-year risk scores before initiating lipid-lowering therapy is a flawed strategy.

The episode delivers a scathing critique of the recent “KetoCT” study, which attempted to suggest that “Lean Mass Hyper-Responders” (lean individuals on keto with sky-high LDL) are safe from heart disease. Simon Hill and Dr. Alan Flanagan deconstruct the data, revealing that despite being “metabolically healthy,” these subjects experienced soft plaque progression at rates nearly four times higher than healthy controls. This reinforces the consensus that elevated ApoB is independently causal for plaque accumulation, regardless of insulin sensitivity.

Further segments explore the mechanics of metabolic health. Dr. Iñigo San Millán details how Type 2 Diabetes begins not with glucose intolerance, but with mitochondrial dysfunction—specifically the inability to oxidize pyruvate and fatty acids—which can be reversed via Zone 2 training. Finally, the episode corrects misconceptions regarding soy and creatine: soy is confirmed as protective against breast cancer recurrence due to its affinity for anti-proliferative estrogen receptors, and creatine is validated as safe for kidneys, with potential high-dose applications for cognitive function during sleep deprivation.

Bullet Summary

  • Optimal Lipids: For true prevention of cardiovascular disease, aim for an LDL cholesterol < 70 mg/dL and triglycerides < 100 mg/dL.
  • The “Thrifty Gene” Hypothesis: 100% of humans carry genes for hypertension, originally evolutionary survival mechanisms now maladapted to modern abundance and sedentary lifestyles.
  • KetoCT Study Reality: Contrary to influencer spin, the KetoCT study showed that lean people with keto-induced high cholesterol had significant soft plaque progression (median 18.9 mm³ increase), debunking the “cholesterol doesn’t matter if you are lean” hypothesis.
  • Plaque Progression: “Metabolically healthy” keto dieters showed plaque progression rates comparable to or worse than intermediate/high-risk populations in other studies.
  • Early Intervention: Waiting for a high 10-year risk score to start statins is outdated; treating elevated ApoB in your 30s prevents the accumulation of plaque that causes events in your 60s.
  • Brain Cholesterol Autonomy: The brain synthesizes its own cholesterol de novo. Aggressively lowering blood LDL (even to < 20 mg/dL) does not harm cognitive function or brain structure.
  • Hypertension Gradient: There is no biological “line” for hypertension; risk increases on a continuum. The ideal blood pressure is < 120/80 mmHg.
  • Lp(a) Management: Lipoprotein(a) is largely genetic. If elevated, you must aggressively manage all other risk factors (ApoB, BP) to offset the risk, as lifestyle changes have minimal impact on Lp(a) levels.
  • Mitochondrial Dysfunction & Diabetes: Type 2 Diabetes is rooted in the mitochondria’s loss of ability to transport and oxidize pyruvate and fatty acids, often preceding insulin resistance.
  • Zone 2 Training Volume: To restore mitochondrial function and metabolic flexibility, aim for 200–300 minutes of Zone 2 training per week.
  • Soy & Cancer: Soy isoflavones preferentially bind to Estrogen Receptor-Beta (anti-proliferative), reducing breast cancer recurrence by ~25%.
  • Environmental Swaps: Replacing beef and lamb with chicken and fish offers the highest reduction in dietary carbon footprint (short of going vegan), though it involves animal welfare trade-offs.
  • Creatine Dosing: Standard muscle maintenance requires 3–5g/day. Acute cognitive benefits (e.g., during sleep deprivation) may require significantly higher doses (10–30g).
  • Creatine & Kidneys: Creatine supplementation raises blood creatinine (a breakdown product), which causes a false positive for kidney stress on standard labs. Cystatin C is a more accurate marker for these individuals.

Claims & Evidence Table

Claim Evidence Provided Assessment
High LDL in “Lean Mass Hyper-Responders” (Keto) is safe. KetoCT study showed median non-calcified plaque volume increased by 18.9 mm³ (approx 4x higher than healthy controls). False/Refuted

The data contradicts the claim; plaque progression was rapid.
Aggressive LDL lowering harms the brain. The brain synthesizes cholesterol de novo and possesses an efflux transporter to remove excess. It does not rely on plasma LDL. Unsupported

Physiologically incorrect; blood-brain barrier isolates brain cholesterol.
Soy consumption increases breast cancer risk. Meta-analyses show soy consumption is associated with a 25% reduction in breast cancer recurrence. Soy binds to ER-beta (anti-proliferative). False

conflicts with human clinical data showing protection.
Zone 2 training prevents Type 2 Diabetes. Zone 2 stimulates mitochondrial pyruvate carriers and fat oxidation enzymes (MCT1, complex I/II), reversing the cellular defect that leads to diabetes. Strong

Supported by bioenergetic mechanism analysis.
Creatine damages kidneys. Creatine supplementation increases creatinine (a metabolite), lowering eGFR calculations falsely. Cystatin C levels remain normal in these subjects. False

Result of lab assay limitations, not renal pathology.
Plant-based diets are superior for the environment. Beef/Lamb have the highest carbon/land footprints. Swapping to chicken/fish or legumes drastically reduces emissions. Strong

Aligns with global environmental data (Our World in Data).

Actionable Insights

  1. Demand Early Lipid Management: Do not wait until middle age. If your ApoB is > 60 mg/dL or LDL > 70 mg/dL in your 30s, discuss initiation of lipid-lowering therapy (statins/PCSK9 inhibitors) to prevent plaque compounding.
  2. Order the Right Labs: Stop relying solely on LDL-C. Request ApoB (target < 60 mg/dL) and Lp(a) (once in a lifetime test) to assess true cardiovascular risk.
  3. Validate Kidney Health: If you take creatine, ask your doctor to test Cystatin C instead of just Creatinine/eGFR to avoid false diagnoses of kidney failure.
  4. Target Blood Pressure: Buy a validated home blood pressure cuff. Aim for an average below 120/80 mmHg. Weight loss is the #1 lifestyle lever for reduction, followed by exercise (12k steps).
  5. Reframe Exercise for Mitochondria: Incorporate 3–4 sessions of Zone 2 cardio (steady state, conversational pace) weekly, totaling 3–4 hours, to specifically target mitochondrial defects associated with aging and diabetes.
  6. Consume Soy Fearlessly: If you have a history of breast cancer or are concerned about it, actively include 1–2 servings of whole soy foods (edamame, tofu, tempeh) daily.
  7. Creatine for Brain Fog: If you are sleep-deprived, consider a higher acute dose of creatine (up to 20–30g split throughout the day) to maintain cognitive performance.
  8. Carbon Footprint Reduction: If you cannot go vegan, swapping red meat (beef/lamb) for poultry or fish is the single most effective dietary change for reducing greenhouse gas emissions.

Technical Deep-Dive

1. Atherogenesis in “Metabolically Healthy” Phenotypes

The “Lean Mass Hyper-Responder” (LMHR) phenotype—characterized by high LDL, high HDL, and low triglycerides—is often touted as benign. The KetoCT study data refutes this. The mechanism of atherosclerosis is driven by the retention of Apolipoprotein B (ApoB) containing particles within the arterial intima.

  • Mechanism: Even in the absence of systemic inflammation (low hs-CRP) or insulin resistance, a high concentration of circulating ApoB particles increases the probability of transcytosis into the sub-endothelial space. Once there, these particles oxidize and aggregate, recruiting macrophages (foam cells) and forming a necrotic core.
  • Data Point: The study showed a median non-calcified plaque progression of 18.9 mm³ over one year. In comparison, the PARADIGM registry shows healthy controls typically progress at < 5 mm³ per year. This confirms that mass action of LDL particles drives plaque, independent of BMI.

2. Mitochondrial Bioenergetics & Diabetes Etiology

Dr. Iñigo San Millán challenges the “Lock and Key” model of insulin resistance as the primary defect in Type 2 Diabetes (T2D).

  • The Defect: He posits the root cause is mitochondrial inflexibility. In early T2D pathology, the mitochondria lose the ability to transport pyruvate (via the Mitochondrial Pyruvate Carrier - MPC) and fatty acids into the matrix for oxidation.
  • Consequence: Since the mitochondria cannot oxidize substrates, glucose and lipids accumulate in the cytosol and blood, leading to hyperglycemia and lipotoxicity.
  • Zone 2 Role: Low-intensity aerobic training specifically upregulates MCT1 (lactate transporter) and mitochondrial complexes I and II, restoring the cell’s ability to clear lactate and oxidize fat/glucose, essentially treating the “cellular congestion” upstream of insulin receptor dysfunction.

3. Soy Isoflavones & Estrogen Receptors

The confusion regarding soy arises from the structural similarity between isoflavones (phytoestrogens) and human estrogen (17β-estradiol).

  • Receptor Selectivity: Human cells possess two primary estrogen receptors: ER-α (alpha) and ER-β (beta).

  • ER-α: Promotes cell proliferation (cancer growth signal) in breast tissue.

  • ER-β: Acts as a tumor suppressor and signals anti-proliferation.

  • Soy Action: Soy isoflavones (genistein/daidzein) have a significantly higher binding affinity for ER-β. Therefore, when soy is consumed, it competitively binds to the beta receptor, potentially blocking stronger endogenous estrogens from binding to alpha receptors, resulting in a net anti-carcinogenic effect.

Fact-Check Important Claims

Claim: “Soy increases breast cancer recurrence risk.”

  • Correction: False.
  • Consensus: The American Cancer Society and the American Institute for Cancer Research (AICR) both state soy is safe.
  • Data: A meta-analysis (e.g., Chi et al., 2013 and subsequent reviews) indicates that post-diagnosis soy food consumption is associated with a statistically significant reduction in recurrence (approx. 25%) and mortality.

Claim: “Creatine causes kidney damage (high creatinine).”

  • Correction: Misleading / False Positive.
  • Mechanism: Creatine spontaneously degrades into creatinine at a rate of ~2% per day. Supplementation increases total creatine stores, thus increasing creatinine output.
  • Verification: Routine eGFR tests estimate kidney function based on creatinine levels. High creatinine due to supplementation leads to a mathematically low eGFR, despite normal renal filtration. Cystatin C is not affected by muscle mass or creatine intake and should be used for verification.

Claim: “ApoB is a better predictor of cardiac risk than LDL-C.”

  • Correction: True/Consensus.
  • Evidence: A 2021 statement by the National Lipid Association confirms ApoB is superior, particularly in discordant cases (e.g., metabolic syndrome, diabetes) where LDL-C may be normal but particle number (ApoB) is high due to small, dense LDL particles.