Dr. Kaeberlein's Optispan Podcast Series - Rapamycin and More

#117

Speaking of this podcast, I would appreciate it if the episodes had less tabloid-like titles. Kind of a turn off.

Screenshot_20251214_174103_Pocket Casts
Screenshot_20251214_174103_Pocket Casts1080×1722 183 KB

2 Likes
#118

They all have to play the attention getting game, and sadly this is what gets viewers.

6 Likes
#119

The latest update on Ora Biomedical:

Gemini Video Summary:

Based on the provided transcript between Dr. Matt Kaeberlein (Optispan) and Dr. Ben Blue (Ora Biomedical), here is the analysis.

Video Analysis: Ora Biomedical & The Million Molecule Challenge

A. Executive Summary

Dr. Ben Blue, CEO of Ora Biomedical, and Dr. Matt Kaeberlein discuss the current state of longevity drug discovery, specifically the limitations of hypothesis-driven research focused on the “Hallmarks of Aging.” They argue that the field has narrowed prematurely, ignoring vast chemical spaces. Ora Biomedical combats this using the “Wormbot,” a robotics and AI platform capable of high-throughput in vivo screening of C. elegans (worms).

The central thesis is that unbiased, massive-scale screening is the only way to find high-magnitude longevity interventions. Ora has screened approximately 10,000 interventions to date—claiming this is already the largest quality dataset in history. Key revelations include the discovery of a molecule that extends lifespan by 60% (outperforming the current gold standard, Rapamycin) and a novel mTOR inhibitor that is more effective than Rapamycin.

Commercially, Ora is pivoting to “resilience” applications—specifically radiation resistance for the US Air Force and Space Force—as a beachhead market to fund longevity research. They argue that longevity therapeutics naturally confer stress resistance, making this a viable regulatory and financial pathway. They estimate that $5 million is required to complete the “Million Molecule Challenge,” a project to map the lifespan effects of one million compounds.

B. Bullet Summary

  • Wormbot Scalability: Ora operates nine “Wormbots,” each capable of screening 100 molecules per week with five replicates, allowing for roughly 1,000 full lifespan experiments per month.
  • The 60% Breakout: Ora has identified a small molecule that extends C. elegans lifespan by 60%, significantly outperforming Rapamycin (the current benchmark).
  • Unbiased Screening: The field currently relies on “mechanism-first” logic (e.g., “does it hit an aging hallmark?”). Ora prioritizes “phenotype-first” logic (“does the animal actually live longer?”).
  • mTOR Variance: Screening reveals massive variance within pathways. While the mTOR pathway is a validated target, individual mTOR inhibitors range from extending lifespan by 50% to shortening it by 30%.
  • Combinatorial Complexity: Combining drugs (e.g., Metformin + X) yields unpredictable synergistic or antagonistic effects that cannot be modeled by current AI without ground-truth biological data.
  • The “Receipts” Problem: Much of the existing aging data is low-quality or lacks visual proof. Ora retains “ground truth” video evidence for every worm screened.
  • Commercial Pivot to Space: To survive the biotech “valley of death,” Ora is targeting radiation resistance for astronauts and the military. This creates a billable indication (acute radiation syndrome/protection) faster than “aging.”
  • Ivermectin Control: The screen blindly identified Ivermectin (an anti-parasitic) as a compound that shortened lifespan by 90%, validating the system’s ability to detect toxicity.
  • Skin Health Application: Topical applications of longevity compounds (like Rapamycin) are being explored for FDA approval via “wrinkle reduction” indications (citing Hayflick Partners).
  • Discovery Cost: Blue estimates the “Million Molecule Challenge” would cost $5 million to complete, potentially identifying hundreds of compounds better than Rapamycin.

D. Claims & Evidence Table

Claim Made in Video Evidence Provided Assessment
Ora has a molecule superior to Rapamycin. Cited internal data showing up to 60% lifespan extension in C. elegans (vs. Rapamycin’s typical lower range). Strong (in model organism); Speculative for humans until mammalian data exists.
Current AI cannot predict longevity interventions effectively. Argument: LLMs and models are trained on open-source data which lacks “ground truth” negative/positive controls and large datasets. Strong. AI is limited by the quality of training data; the longevity dataset is historically sparse.
$5 Million could fund 1 million lifespan experiments. Extrapolation based on current Wormbot operating costs and throughput capabilities. Plausible. Assuming economies of scale hold and hardware/labor costs remain linear.
Longevity interventions confer radiation resistance. Initial screening data showing lifespan-extending molecules also protect worms from UV radiation. Strong. Scientific consensus supports the link between stress response pathways (e.g., DNA repair) and longevity.
“Polysi” (phonetic) is a better mTOR inhibitor. Cited data from a crowdsourced experiment by “Chris” (likely Chris Kowalski/Rapamycin.news) finding a specific inhibitor outperforms Rapamycin. Promising. Needs peer-reviewed validation and specific compound identification.
In vivo (worm) data translates better than cell culture. Intuition/Argument: Whole organisms capture systemic complexity (metabolism, tissue interaction) that cell cultures miss. Speculative. While logical, C. elegans lack circulatory/adaptive immune systems, making translation to humans difficult.

E. Actionable Insights

For the Biotech Investor & Entrepreneur

  1. Evaluate “Resilience” Plays: Look for longevity companies pivoting to “stress resistance” (radiation, wound healing, TBI) to bypass the FDA’s refusal to recognize aging as a disease. This is a viable path to market.
  2. Demand “Ground Truth” Data: When evaluating AI drug discovery firms, ask for the proprietary biological dataset they trained on. If it’s public data (DrugAge), their model is likely weak.
  3. Monitor “Polysi” & Novel mTOR Inhibitors: Keep a watch for the publication of the specific mTOR inhibitors identified by Ora that outperform Rapamycin. This represents a new IP class.
  4. Skepticism of Mechanism-Only Pitches: Be wary of pitch decks that show pathway activation (e.g., “We activate Sirtuins”) without showing lifespan extension in an animal model. Mechanism Outcome.
  5. Skin Health as a Wedge: Topical Rapamycin (and next-gen analogs) for “wrinkles” is a near-term commercializable longevity product. Follow companies like Hayflick Partners.

For Longevity Research & Health

  1. Support Open Source Screening: The “Million Molecule Challenge” allows individuals to sponsor molecule testing. This is a mechanism to crowdsource data that NIH refuses to fund.
  2. Combinatorial Caution: Be extremely cautious with “biohacking” stacks. Data shows that combining two beneficial drugs (e.g., Metformin + X) can frequently cancel benefits or cause toxicity.
  3. Wait for Mammalian Validation: The 60% extension in worms is exciting, but do not self-experiment with novel compounds until mouse model data (specifically the ITP or similar rigor) confirms safety and efficacy.

H. Technical Deep-Dive

High-Throughput Phenotypic Screening vs. Target-Based Discovery

The industry standard for drug discovery is Target-Based: identify a protein (e.g., mTORC1), find a molecule that binds to it, and assume biological efficacy.

  • The Flaw: This ignores off-target effects, bioavailability, and organism-level complexity. As noted in the transcript, many mTOR inhibitors technically hit the target but shorten lifespan due to toxicity or poor pharmacokinetics.

Ora Biomedical utilizes Phenotypic Screening:

  1. Model: C. elegans (Nematode). Short lifespan (3 weeks), fully mapped connectome, genetic conservation with humans (e.g., Insulin/IGF-1 signaling, mTOR, Autophagy pathways).
  2. Method: Robotics (Wormbot) capture longitudinal imaging of thousands of populations simultaneously.
  3. Endpoint: All-cause mortality (Lifespan). This integrates all biological failures (cancer, neurodegeneration, metabolic collapse) into a single binary metric: dead or alive.

The Radiation-Longevity Crossover

The technical rationale for the pivot to radiation resistance involves the Hormesis and Stress Response overlap.

  • Mechanism: Interventions that downregulate growth pathways (like mTOR) typically upregulate maintenance pathways (Autophagy, DNA repair).
  • Application: By pre-treating with a longevity drug, the organism’s cells enter a “protected state,” prioritizing DNA repair over replication. When hit with ionizing radiation (or UV in the screen), the organism survives damage that would otherwise induce apoptosis or senescence.

I. Fact-Check Important Claims

  • Claim: “Rapamycin is the best we have.”

  • Status: True. In terms of reproducible, pharmacological lifespan extension in mammals (mice), Rapamycin is the gold standard, consistently showing 10-25% extension in the NIA Interventions Testing Program (ITP).

  • Claim: “Astronauts arrive sick… damage accrued from radiation.”

  • Status: Supported. Spaceflight Associated Neuro-ocular Syndrome (SANS), muscle atrophy, and increased cancer risk due to Galactic Cosmic Rays (GCR) are documented NASA concerns. Accelerated aging markers (telomere length changes, DNA methylation) have been observed (e.g., the NASA Twins Study).

  • Claim: “Ivermectin shortened lifespan by 90%.”

  • Status: True. Ivermectin is a glutamate-gated chloride channel agonist. In invertebrates (C. elegans and parasites), this causes paralysis and death. It is safe in humans because we have a blood-brain barrier and different channel structures, but it is lethal to worms.

2 Likes
How to Stop or Reverse Skin Aging (2026)
Anyone purchased and tried Rilmenidine?
#120

This was interesting… another mTOR inhibitor company for topical use to prevent skin aging. Seems like ongoing rapamycin use for prevention of skin aging is probably not a bad bet. This is the second company offering this type of product and going for FDA approval. Matt is on the advisory board, he notes.

https://www.hayflickpartners.com

2 Likes
How to Reverse Skin Aging (2025)
#121
2 Likes
#122

Everything I do for Healthspan (and why I skip THESE Supplements)

Gemini Pro Video Summary:

Here is the summary and analysis of the provided transcript.

A. Executive Summary

In this episode of the Optispan podcast, the host (Matt Kaeberlein) details his personal health protocol as of late 2025, covering lifestyle pillars, supplements, and pharmaceutical interventions. His core philosophy emphasizes a strict hierarchy of efficacy: Foundational Lifestyle Pillars (Eat, Move, Sleep, Connect) provide the vast majority of health benefits, followed by targeted medications, with supplements ranking a distant third due to weak regulatory oversight and inconsistent efficacy.

Regarding lifestyle, he adheres to a whole-food diet minimizing added sugars, engages in daily Zone 2 cardio and resistance training 3-4 times per week, and prioritizes sleep hygiene by eliminating alcohol. He identifies “Connection” as his weakest pillar but is actively working on relationship building.

His supplement strategy is highly skeptical. He utilizes a small stack including Omega-3, Vitamin D, Calcium Alpha-Ketoglutarate (Ca-AKG), Methylfolate, Lithium Orotate, and Creatine. He explicitly rejects popular “hype” supplements such as NAD+ precursors, Resveratrol, and general antioxidants, citing a lack of compelling clinical data or potential counter-productivity.

On the pharmaceutical front, he employs a preventative, risk-reward approach. He utilizes Testosterone Replacement Therapy (TRT) for quality of life and Rapamycin (cyclic dosing) for longevity/geroprotection. Notably, he uses SGLT2 inhibitors (Jardiance) and PCSK9 inhibitors (Repatha) for metabolic and cardiovascular prophylaxis, arguing that SGLT2s have superior longevity data (in mice) compared to Metformin, which he has discarded. He advocates for finding physicians willing to engage in proactive, preventative risk assessment rather than reactive disease management.

B. Bullet Summary

  • Hierarchy of Health: Lifestyle modifications (diet, exercise, sleep) are the primary drivers of healthspan; supplements are mostly incremental or “noise.”
  • Nutritional Rule #1: Religiously read labels to avoid added sugars; prioritize fiber (e.g., keto bread) and high-quality protein (salmon, poultry).
  • Training Volume: Daily activity is non-negotiable. 30 minutes of Zone 2 cardio daily, plus resistance training 3-4 times per week focusing on compound movements.
  • Alcohol Elimination: Alcohol is identified as a primary disruptor of sleep quality; removing it is a high-yield intervention.
  • Supplement Skepticism: The supplement industry is described as “dishonest and deceptive.” Third-party testing (e.g., ConsumerLab) is essential for purity.
  • Creatine Utility: Recommended for everyone (5g/day) for muscle mass preservation and potential cognitive benefits (buffering energetic stress in the brain).
  • Lithium for Brain Health: Low-dose Lithium Orotate (5mg) is added based on epidemiological data linking trace lithium to reduced Alzheimer’s risk.
  • SGLT2 over Metformin: Metformin is dismissed for longevity in healthy individuals due to failure in the Interventions Testing Program (ITP); SGLT2 inhibitors (Jardiance) are preferred for their lifespan extension data in mice.
  • Lipid Management: Soft plaque detection prompted the use of Repatha (PCSK9 inhibitor) to aggressively lower ApoB, superior to statins for this specific profile.
  • Rapamycin Protocol: Adheres to a cyclic protocol (e.g., 8mg/week for 3 months on, followed by a washout period) to mitigate immune risks while targeting sterile inflammation.
  • Testosterone Micro-dosing: Switched from weekly to daily TRT injections (6 days/week) to mitigate hematocrit spikes and stabilize serum levels.
  • GLP-1/GIP Agonists: Experimented with low-dose Tirzepatide (Zepbound/Mounjaro); noted appetite suppression and weight loss but discontinued to assess baseline.
  • Preventative Cardiology: Standard lipid panels are insufficient; specifically measure ApoB and utilize coronary CT angiograms with contrast to detect soft plaque.

D. Claims & Evidence Table

Claim Evidence Cited Assessment
Alcohol disrupts sleep quality. Personal biometrics (wearables) and observations of patients/clients. Strong (Supported by broad consensus and sleep architecture data).
SGLT2 inhibitors (e.g., Canagliflozin) extend lifespan. Murine studies from the Interventions Testing Program (ITP). Strong (in mice); Speculative but plausible for human longevity.
Metformin is NOT a longevity drug for healthy individuals. Failure to extend lifespan in ITP mouse studies; lack of human data outside of diabetics. Strong (Contradicts the TAME trial hypothesis but aligns with rigorous animal data).
Creatine benefits brain health. Emerging evidence on energetic buffering during cognitive stress/sleep deprivation. Speculative/Promising (Plausible mechanism, clinical data still maturing).
Lithium Orotate reduces Alzheimer’s risk. Epidemiological correlation (water supply) and recent biochemical papers (e.g., Bruce Yankner’s lab). Speculative (Strong correlation, mechanism identified, but lacks RCTs).
Ca-AKG reduces biological age/frailty. Mouse studies (frailty reduction) and anecdotal exercise tolerance (Brian Kennedy). Mixed (Good for healthspan/frailty in mice; lifespan data is weak).
Tadalafil lowers all-cause mortality. UK Biobank data analysis. Strong Association (Correlation exists, likely due to circulatory/cardiovascular benefits).

E. Actionable Insights

  1. Stop “Hacking” & Start “Stacking” Pillars: Focus 90% of effort on Eat, Move, Sleep, and Connect. Do not rely on supplements to fix lifestyle deficits.
  2. Eliminate Added Sugars: Scrutinize nutrition labels. If it has added sugar, do not bring it into the house.
  3. Monitor ApoB, Not Just LDL: Request ApoB testing in your quarterly blood panels for a true measure of atherogenic particle burden.
  4. Consider Coronary CT Angiogram: If over 40, consider a scan to detect soft plaque, which traditional calcification scans (CAC) miss.
  5. Micro-dose Creatine: Take 5g of Creatine Monohydrate daily, regardless of whether you lift weights, for potential neuroprotective effects.
  6. Zone 2 is Daily Hygiene: Treat 30 minutes of low-intensity cardio (Zone 2) as a daily requirement, similar to brushing teeth.
  7. Optimize TRT Frequency: If on Testosterone Replacement Therapy, consider daily or every-other-day micro-dosing to prevent hematocrit spikes and estrogenic side effects.
  8. Evaluate SGLT2 Inhibitors: Discuss SGLT2 inhibitors (like Empagliflozin) with your doctor for glucose management and potential geroprotection instead of Metformin.
  9. Check Supplement Purity: Use services like ConsumerLab.com to verify that your supplements do not contain heavy metals or impurities.
  10. Cycle Rapamycin: If using Rapamycin off-label, consider a cyclic approach (e.g., 3 months on, 3 months off) to balance mTOR inhibition with immune function.

H. Technical Deep-Dive

1. SGLT2 Inhibitors vs. Metformin (Geroprotection Mechanisms)
The speaker prioritizes Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors (e.g., Empagliflozin, Canagliflozin) over Metformin.

  • Mechanism: SGLT2 inhibitors block glucose reabsorption in the proximal tubule of the kidney, inducing glycosuria (excretion of glucose in urine) and natriuresis. This lowers plasma glucose and insulin levels independent of insulin secretion.
  • Longevity Data: The Interventions Testing Program (ITP) demonstrated that Canagliflozin extends median lifespan in male mice significantly. Conversely, Metformin failed to consistently extend lifespan in ITP heterogenous mouse cohorts, suggesting its “anti-aging” reputation may be an artifact of treating metabolic dysfunction rather than slowing fundamental aging.

2. Lithium Orotate & Neuroprotection

  • Mechanism: Lithium is a potent inhibitor of Glycogen Synthase Kinase-3 beta (GSK-3β). Hyperactive GSK-3β is implicated in the hyperphosphorylation of Tau protein (leading to neurofibrillary tangles in Alzheimer’s) and the production of amyloid-beta.
  • Dosing: The speaker uses 5mg (micro-dose) compared to psychiatric doses (900mg+). The hypothesis is that chronic, low-grade inhibition of GSK-3β via trace lithium mimics the epidemiological benefits seen in populations with naturally high lithium water content.

3. PCSK9 Inhibition (Repatha)

  • Mechanism: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors (LDLR) on hepatocytes, promoting their lysosomal degradation. By inhibiting PCSK9, Repatha increases the recycling of LDLRs to the cell surface, drastically increasing the clearance of LDL particles (and thus ApoB) from the bloodstream. This is a more targeted and potent mechanism for lowering atherogenic burden than HMG-CoA reductase inhibitors (statins).

I. Fact-Check Important Claims

Claim: “Metformin extends lifespan in diabetics but not non-diabetics.”

  • Status: Contested/Likely Accurate.
  • Analysis: The original Bannister et al. (2014) study suggested diabetics on Metformin lived longer than non-diabetics. However, subsequent analyses have suggested this was due to selection bias (immortal time bias) and rigorous controls do not show lifespan extension in healthy subjects. The ITP data in mice supports the speaker’s skepticism regarding Metformin as a general geroprotector.

Claim: “Creatine has cognitive benefits beyond muscle.”

  • Status: Supported by Emerging Evidence.
  • Analysis: Systematic reviews indicate Creatine supplementation can improve short-term memory and intelligence/reasoning in healthy individuals, particularly under conditions of stress or sleep deprivation.
  • Reference: Avgerinos et al. (2018), Experimental Gerontology.

Claim: “Rapamycin extends lifespan in mice.”

  • Status: Consensus Fact.
  • Analysis: Rapamycin is the most robust pharmacological intervention for lifespan extension in mice, reproducible across multiple sites (ITP), strains, and genders. It functions via inhibition of mTORC1 (mechanistic target of rapamycin complex 1), a central regulator of cell growth and metabolism.
5 Likes
#124

Whether or not it has any protection from Alzheimer’s (it probably does), it certainly raised the anger threshold in me, and that in and of itself is a benefit for me. Anger reliably raises both cortisol and blood pressure. So, low-dose lithium could extend the lifespan of some people.

Repeated blood pressure surges and higher BP variability track with higher mortality

Even when a person’s average BP isn’t terrible, greater variability (big ups/downs across visits, days, or home readings) is associated with higher risk of stroke, coronary disease, and all-cause mortality in meta-analyses and large cohorts.

Ref1

2 Likes
#125

Matt talks about this forum just after the 50 minute mark in this video :+1:

6 Likes
#126

Preventive Failure: How Modern Healthcare Misses Disease Early

Gemini AI Video Summary and Analysis:

Here is the summary and analysis of the provided transcript.

Optispan Podcast: The Clinical Reality of Healthspan Medicine

Host: Matt Kaeberlein | Guest: Dr. Nikki Byrne (Clinical Director, Optispan)

A. Executive Summary

This conversation explores the operational definition of “Healthspan Medicine” as distinct from traditional “reactive disease care.” Dr. Nikki Byrne argues that the standard medical model is fundamentally misaligned with longevity; it allocates resources to crisis management (e.g., stroke rehabilitation) rather than upstream prevention. A central thesis is that “reference range” does not equal “optimal.” The discussion highlights that standard primary care often misses early pathology—such as insulin resistance or carotid plaque—because it relies on lagging indicators like A1C or basic lipid panels.

The Optispan model, as detailed by Byrne, utilizes a “Gateway Day” involving comprehensive diagnostics: advanced blood panels (ApoB, fasting insulin), Point of Care Ultrasound (POCUS), DEXA scans for visceral fat, genetic screening (APOE, MTHFR), and functional movement assessments. The dialogue emphasizes that granular data allows for precise pharmacological and lifestyle interventions. Byrne defends the use of off-label pharmacotherapies for prevention in high-risk but “clinically normal” phenotypes, including GLP-1 agonists for visceral fat reduction in non-obese patients, SGLT2 inhibitors for glucose modulation, and PCSK9 inhibitors for aggressive lipid lowering. The conversation concludes with a critique of the longevity industry’s extremes—specifically dangerous hormone protocols for the elderly—while advocating for a data-driven, patient-autonomous approach to extending healthspan.

B. Bullet Summary

  • The Reactive Trap: The current healthcare system offers minimal interaction (one visit/year) until a catastrophic event occurs, at which point resources become unlimited but often too late to reverse decline.
  • Reference Range vs. Optimal: A patient can have “normal” LDL and A1C but still possess significant carotid plaque and insulin resistance; standard reference ranges are population averages, not health targets.
  • Insulin as a Sentinel: Fasting insulin is a superior early warning marker compared to Hemoglobin A1C. A1C is a lagging indicator; the body can compensate with hyperinsulinemia for years before blood glucose rises.
  • Visceral Adiposity (TOFI): “Thin Outside, Fat Inside” is a critical phenotype. Individuals with normal BMI but high visceral fat (detected via DEXA) are at high metabolic risk.
  • The Utility of GLP-1s: Byrne utilizes GLP-1 agonists (e.g., Tirzepatide) not just for obesity, but to specifically target visceral fat and inflammation in metabolically unhealthy normal-weight individuals.
  • SGLT2 Inhibitors for Longevity: These diabetes drugs (e.g., Empagliflozin) are used off-label for pre-diabetes and potential lifespan extension, citing animal data (ITP) and kidney/CV protection in humans.
  • Aggressive Lipid Management: When statins are insufficient or untolerated, PCSK9 inhibitors (Repatha) are used to crush ApoB/LDL levels to prevent plaque accumulation, even in primary prevention contexts.
  • Diagnostic Imaging: Point of Care Ultrasound (POCUS) is essential for screening thyroid nodules, fatty liver, and carotid intimal thickness, identifying risks missed by blood work.
  • Oral-Systemic Link: Intraoral scanning is included because periodontal inflammation is strongly correlated with cardiovascular disease and dementia risk.
  • Sleep Quality over Quantity: Using tracking (Oura), the focus shifts to deep and REM sleep duration rather than just time in bed; alcohol is identified as a primary disruptor of sleep architecture.
  • Rapamycin Protocol: Used cyclically (e.g., weekly) for longevity. The clinical view is that the risk profile at low doses is minimal compared to the potential upside for immune and geroprotective effects.
  • Creatine Utility: Recommended for men and women (especially post-menopausal) for muscle maintenance and emerging evidence of cognitive support.
  • Patient Autonomy: The clinic supports patient experimentation (e.g., specific peptides) if the safety profile is acceptable, prioritizing the therapeutic alliance over paternalism.

C. Technical Deep-Dive

1. Insulin Resistance & Hyperinsulinemia

Byrne highlights the discrepancy between A1C and Fasting Insulin. Mechanistically, insulin resistance manifests as the downregulation of insulin receptors or defects in the PI3K/AKT signaling pathway in peripheral tissues (muscle, adipose).

  • The Lag: To maintain euglycemia (normal blood sugar), pancreatic -cells undergo hypertrophy and hyper-secrete insulin (compensatory hyperinsulinemia).
  • Clinical Consequence: Standard care measures glucose/A1C, which only elevate after -cell compensation fails. Measuring fasting insulin identifies the metabolic dysfunction years prior to Type 2 Diabetes diagnosis.

2. PCSK9 Inhibition (Repatha)

The podcast discusses using Repatha for patients with high Lp(a) or resistant LDL.

  • Mechanism: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors (LDLR) on the hepatocyte surface, promoting their lysosomal degradation.
  • Intervention: Monoclonal antibodies (Evolocumab) bind PCSK9, preventing it from binding LDLR. This increases LDLR recycling to the cell surface, enhancing the clearance of LDL-C from the plasma.

D. Claims & Evidence Table (Adversarial Peer Review)

Role: Longevity Scientist / Peer Reviewer.
Standard: Strict evidence hierarchy.

Claim from Video Speaker’s Evidence Scientific Reality (Best Available Data) Evidence Grade Verdict
“Fasting insulin is superior to A1C for early detection.” Clinical observation of normal A1C in insulin-resistant patients. Supported. The Kraft patterns demonstrate hyperinsulinemia precedes hyperglycemia by years. (Crofts et al., Diabesity, 2016). B/C Strong Support
“Oral health (gum inflammation) correlates with heart disease/dementia.” Mention of emerging data. Supported (Correlation). High-quality cohort studies link periodontitis to atherosclerotic CVD and Alzheimer’s. Causation via systemic inflammation is the leading hypothesis. (Hastings et al., Alzheimers Dement, 2021). C Plausible
“GLP-1s reduce visceral fat in non-obese (‘skinny fat’) people.” Clinical practice/observation. Translational Gap. Strong data exists for obese populations (SURMOUNT/STEP trials). Data for lean individuals with visceral adiposity is mechanistically sound but lacks specific RCTs. E Speculative (in this population)
“SGLT2 inhibitors (Jardiance) increase longevity.” Cites mouse data; human kidney/CV benefits. Mixed. NIA ITP confirmed lifespan extension in male mice (Miller et al., 2020). Human data shows reduced CV mortality and renal decline (EMPA-REG), but “aging” reversal is unproven in humans. D (Mice) / A (CV Mortality) Plausible (for CV protection)
“Low-dose Lithium (Orotate) is safe/beneficial.” Cites Nature paper; groundwater studies. Speculative. Microdose lithium (1-5mg) is likely safe (unlike psychiatric doses). Longevity benefits are based on epidemiological groundwater correlations and worm/fly studies. Human RCTs for aging are absent. C/D Experimental
“Topical Rapamycin reverses skin aging.” Cites pilot study. Emerging. A small RCT (Chung et al., 2019) showed reduced p16INK4a (senescence marker) and improved collagen. Sample size was small (n=36). B (Small RCT) Plausible
“Gallery Test false positive rate is 50%.” Cites general stats/NYT article. Accurate. In the PATHFINDER study, the Positive Predictive Value (PPV) was approximately 38-43%. A positive result is more likely to be false than true in asymptomatic screening. B Factually Correct
“Hormones of a 25-year-old in an 80-year-old are dangerous.” Clinical judgment/physiology. Consensus Support. High-dose systemic HRT in elderly women well past menopause is linked to increased risk of stroke/VTE (WHI re-analysis). A Strong Support

E. Actionable Insights (Pragmatic & Prioritized)

Top Tier (High Confidence / Standard of Care +)

  1. Diagnostic Upgrade: Do not settle for a standard lipid panel. Demand ApoB and Lp(a) testing once to assess genetic risk.
  2. Metabolic Sentinel: Measure Fasting Insulin alongside glucose. If A1C is normal but Insulin is >5-7 uIU/mL, intervene immediately.
  3. Visceral Fat Check: BMI is insufficient. Use DEXA to identify visceral adipose tissue (VAT). Even if thin, high VAT requires lifestyle or pharmacological intervention.
  4. Periodontal Care: Treat flossing and dental hygiene as cardiovascular prevention.
  5. Sleep Hygiene: Eliminate alcohol within 3-4 hours of bed. Prioritize deep sleep windows (early night) by maintaining consistent bedtimes.

Experimental / Optimization (Risk/Reward Managed)

  1. Creatine Monohydrate (5g/day): Low downside. Benefits muscle preservation and likely cognitive function, particularly during sleep deprivation or menopause.
  2. SGLT2 Inhibitors (e.g., Empagliflozin): Consider off-label use for pre-diabetes or longevity if renal function allows, monitoring for UTIs and hypotension.
  3. GLP-1 Agonists (Low Dose): For “TOFI” (Thin Outside Fat Inside) phenotypes, consider low-dose intervention to strip visceral fat, even if not clinically obese.
  4. Rapamycin (Cyclic): Weekly low-dose protocols (e.g., 6mg/week) for geroprotection. Strict Requirement: Must be done under physician supervision to monitor lipids, glucose, and immune function.

Avoid

  • “25-Year-Old Hormones” after 65: Avoid aggressive, high-dose hormone replacement therapies that aim to mimic youth levels in elderly physiology, specifically regarding estrogen/progesterone in women decades past menopause due to stroke/clotting risk.

I. Fact-Check: Important Claims

Claim: “A patient had a normal lipid panel but significant plaque on ultrasound.”

  • Verification: This highlights the discordance between LDL-C and atherosclerotic risk. Approximately 50% of heart attacks occur in people with “normal” LDL levels. Plaque burden (measured by CCTA or Ultrasound) is the direct disease substrate, whereas LDL is a probabilistic risk factor.
  • Correction: None needed. This aligns with current cardiology consensus moving toward imaging-guided prevention (SCCT guidelines).

Claim: “Magnesium helps with sleep and bowel function.”

  • Verification: Magnesium Glycinate or Threonate is often used for sleep/anxiety, while Magnesium Citrate/Oxide is osmotic and aids bowel movement.
  • Nuance: The transcript doesn’t specify the form, but the physiological claim is accurate depending on the chelation used.

Claim: “Oura ring detects sleep staging accuracy.”

  • Verification: While Oura and other wearables are excellent for patterns and duration, their accuracy in distinguishing specific sleep stages (REM vs. Deep) compared to Polysomnography (PSG) is generally 60-65%.
  • Context: Dr. Byrne correctly notes they use it for “pattern recognition” rather than medical diagnosis, acknowledging the limitations.
3 Likes
#127

A good podcast, especially for women. Also, some interesting recipes that I may try.

Protocol Initialized: Biotech Analyst & Peer Reviewer Mode Active

I have processed the transcript featuring Shannon Anderson and Matt Kaeberlein. The following is a rigorous audit of the N=1 case study presented, filtering for survivorship bias and genetic outliers while extracting clinically relevant data.

I. Executive Summary

Subject: Female, 63 years old. Background of eating disorders (anorexia/bulimia) and “skinny-fat” phenotype.
Core Thesis: Transition from aesthetic-driven health (starvation/cardio) to performance-driven longevity (resistance training/macronutrients/hormone optimization).

The subject demonstrates a successful reversal of sarcopenic trajectory and metabolic dysfunction (pre-diabetic biomarkers) through a multimodal intervention. Key drivers identified are aggressive Menopausal Hormone Therapy (MHT), including testosterone; high-intensity resistance training (HIRT) focused on progressive overload; and a high-protein/high-fiber nutritional framework.

Critical Caveat: The subject exhibits significant genetic outliers, specifically a 90th percentile VO2 max despite zero aerobic conditioning. This represents a dangerous translational gap for the general population; replicating her “no cardio” protocol would likely result in cardiovascular deconditioning for the average phenotype. The protocol is high-efficacy for body recomposition (muscle gain/fat loss) but requires careful modulation regarding fiber intake and hormone safety profiles.

II. Insight Bullets

  • The “Skinny Fat” pathology: Historic reliance on caloric restriction and purging created a phenotype of low visceral fat but critical lean mass deficiency (sarcopenia), masking metabolic dysfunction until late middle age.
  • MHT & Cognitive Function: Subject reports immediate clearance of “brain fog” upon initiation of Estradiol/Progesterone. This aligns with the “critical window” hypothesis regarding estrogen receptors in the hippocampus and prefrontal cortex.
  • Testosterone in Women: The addition of testosterone was the inflection point for muscle hypertrophy and libido recovery. This is an under-prescribed intervention in female longevity due to virilization fears, which were managed here via dosage control.
  • Sleep Apnea (OSA) Masquerading as Insomnia: Subject relied on sedatives (Ambien/Trazodone) for years, masking undiagnosed OSA. Mechanical intervention (CPAP) combined with sedative tapering increased sleep duration from 5 to 9 hours.
  • Sedative-Dementia Link: The transcript correctly identifies the correlation between chronic Z-drug/anticholinergic use and neurodegenerative risk, necessitating a deprescribing protocol.
  • Protein Thresholds: Intake of ~1g/lb body weight (125g) utilized to overcome anabolic resistance common in post-menopausal women.
  • Fiber Outlier: Subject consumes ~75g fiber/day. This is >3x the RDA. While effective for her lipid/glycemic control, this dosage often induces severe GI distress in IBS cohorts, making her tolerance an anomaly.
  • The “Trainer Tax”: Outsourcing programming and safety monitoring to a professional was cited as the primary adherence mechanism for heavy lifting, mitigating injury risk in an osteopenic/arthritic context.
  • Metabolic Volatility: A 2-month deviation from the protocol (stress-induced undereating/carb-loading) resulted in immediate regression to pre-diabetic HbA1c levels, highlighting the fragility of metabolic health in aging populations despite previous “fitness.”

III. Adversarial Claims & Evidence Table

Search Query Parameters: [Topic] meta-analysis clinical trial 2022-2026

Claim from Video Scientific Reality (Current Data) Evidence Grade Verdict
“Resistance training alone maintains 90th percentile VO2 max (no cardio).” VO2 max is ~50% heritable. While resistance training improves VO2 max in the untrained, it rarely achieves elite levels without aerobic stimulus. Subject is a genetic outlier. C (Cohort/Genetics) Unsupported (as a protocol)
“Testosterone therapy in women drives muscle gain and sexual function.” Global Consensus Statement (2019) supports T for Hypoactive Sexual Desire Disorder (HSDD). Muscle effects are dose-dependent and require stimulus (verified here). Long-term safety data is developing. A (HSDD) / B (Muscle) Strong Support
“Estrogen replacement resolves brain fog/memory issues.” Estrogen modulates glucose transport in the brain. Data supports symptom relief (hot flash-associated fog) but is mixed on preventing dementia if started late (>10 yrs post-menopause). B (Symptomatic) Plausible
“Sleep medications (Ambien) are linked to memory problems/Alzheimer’s.” Strong correlation between chronic use of Z-drugs/Benzodiazepines and incident dementia. Mechanisms include suppression of slow-wave sleep and anticholinergic burden. C (Observational) Safety Warning
“75g of fiber daily is optimal for gut health/metabolism.” High fiber lowers CVD/Diabetes risk. However, doses >50g often cause malabsorption of minerals and GI distress. 75g is clinically extreme for an IBS patient. B (Dose-Response) Experimental (Outlier)
“Resistance training does not cause ‘bulking’ in women without high-dose hormones.” Female physiology lacks the androgenic profile to support massive hypertrophy without exogenous anabolic agents. “Bulking” fear is scientifically unfounded. A (Physiology) Strong Support

IV. Actionable Protocol (Prioritized)

This protocol filters out the subject’s genetic anomalies to provide a safe, scalable framework.

High Confidence Tier (Level A/B Evidence)

  1. Sleep Architecture Restoration:
  • Action: Immediate screening for Obstructive Sleep Apnea (OSA) if snoring or daytime fatigue is present, regardless of BMI.
  • Protocol: Prioritize CPAP/APAP over pharmaceutical sedatives. Taper off Z-drugs (Ambien) under medical supervision to restore Slow Wave Sleep (SWS).
  1. Hypertrophy-Focused Resistance Training:
  • Frequency: 3x/week, 50-60 minutes.
  • Selection: Compound movements (Squats, RDLs, Rows, Press).
  • Intensity: Close to failure (RPE 8-9). “Toning” is a myth; heavy loading is required for osteogenic and metabolic adaptation.
  1. Protein-Centric Nutrition:
  • Dosage: 1.6g to 2.2g per kg of body weight (approx 0.7-1g per lb).
  • Timing: Distributed across 3-4 meals to maximize Muscle Protein Synthesis (MPS) spikes, essential for overcoming age-related anabolic resistance.

Experimental Tier (Level C Evidence / Clinical Judgement)

  1. Hormone Optimization (Female):
  • Estrogen/Progesterone: Consider for vasomotor symptom management and potential neuroprotective windows (early post-menopause). Requires oncology risk assessment.
  • Testosterone: Trial for HSDD or refractory sarcopenia. Monitor lipid panels and virilization symptoms strictly.
  1. Fiber Ramping:
  • Protocol: Aim for 35-50g from whole foods.
  • Warning: Do not jump to 75g immediately. Titrate up to avoid bowel obstruction or severe IBS flares.

Red Flag Zone (Do Not Replicate)

  • The “Zero Cardio” Approach: Do not assume resistance training covers cardiovascular needs. The subject’s VO2 max is a genetic anomaly. Combined concurrent training (Resistance + Zone 2 Cardio) remains the gold standard for longevity.
  • Reliance on “Metabolism Bars”: While convenient, whole food sources are superior for satiety and micronutrient density. Use processed fiber/protein only as emergency contingencies.

V. Technical Mechanism Breakdown

1. Anabolic Resistance & Sarcopenia

The subject references the difficulty of building muscle past age 60. Aging muscle becomes “anabolic resistant,” meaning the threshold for stimulating Muscle Protein Synthesis (MPS) increases.

  • Mechanism: Blunted sensitivity of the mTORC1 pathway to leucine and mechanical tension.
  • Correction: This necessitates higher protein intakes (the 1g/lb target) and higher mechanical tension (heavy lifting) compared to younger individuals to achieve the same hypertrophic response.

2. Estrogen & Cognitive Function

The subject reported “brain fog” clearance. Estrogen receptors (ER$\alpha$ and ER$\beta$) are dense in the hippocampus (memory) and prefrontal cortex (executive function).

  • Mechanism: Estradiol supports cerebral glucose metabolism (CMRglc) and mitochondrial function in neurons. The drop in estradiol during menopause is linked to a “bioenergetic crisis” in the brain, manifesting as fog or cognitive slowing. HRT mitigates this hypometabolism.

3. Sleep Apnea (OSA) & Glymphatic Clearance

The subject’s use of CPAP improved sleep duration and quality.

  • Mechanism: OSA causes intermittent hypoxia and sleep fragmentation, preventing the brain from entering deep NREM sleep. The glymphatic system, which clears neurotoxins like beta-amyloid, is primarily active during deep NREM. Untreated OSA and the use of sedatives (which alter sleep architecture) impair this clearance, increasing Alzheimer’s risk.
#128

The recipe / food ideas from the podcast:

Protocol Initialized: Biotech Analyst & Peer Reviewer Mode Active

I have scanned the transcript for nutritional formulations. The subject, Shannon Anderson, details one specific “recipe” framework used for bulk meal preparation to hit her high-protein (125g) and high-fiber (75g) targets.

The “Naked Chicken” Nutrient-Dense Matrix

Objective: High-protein, high-fiber, polyphenol-rich meal prep optimized for time-restricted professionals.

Classification: Functional Whole Food Matrix (Level C - Anecdotal Utility).

Ingredients:

  • Protein Base: Chicken breast (Skinless, boneless).
  • Vegetable Load:
    • Kale (Cruciferous/Fiber).
    • Carrots (Carotenoids).
    • Bell Peppers (Vitamin C).
    • Sweet Potato (Resistant Starch/Complex Carb).
  • Flavor/Texture Modifiers:
    • Dried Currants (Polyphenols/Palatability).
    • Vegan Mayonnaise (Fat source for binding/satiety).
  • Delivery System: High-protein, high-fiber tortillas.

Protocol (Preparation):

  1. Thermal Processing: Bake the chicken breast until fully cooked.
  2. Mechanical Homogenization: Place cooked chicken and raw/prepped vegetables into a food processor.
  3. Pulse: Process until a consistent, spreadable mixture is achieved (similar to a dense chicken salad).
  4. Assembly: Portion into tortillas and store for rapid deployment.

Nutritional Analysis (Estimated per serving):

  • Macronutrients: High Protein (>30g), Moderate Carb (Fiber-heavy), Moderate Fat.
  • Micronutrients: Vitamin A, C, K, Potassium, Beta-carotene.
  • Biotech Note: The mechanical processing (food processor) increases the surface area for digestive enzymes, potentially aiding absorption in compromised guts (IBS), though it may slightly increase the glycemic index of the vegetables compared to eating them whole.
1 Like
#129

Pro tip from the vegan:
If you are going to try vegan mayo for the first time, I suggest Just Mayo

1 Like
#130

Optimized Video Analysis: Supplement Tier List & Longevity Protocols

I. Executive Summary

Context: An analysis of a February 2026 Optispan podcast segment ranking 13 longevity supplements. The host, a longevity researcher, pivots from general enthusiasm to a rigorous risk/reward framework, heavily penalizing interventions lacking human efficacy data or facing manufacturing opacity.

Core Thesis: The “Supplement Graveyard” is growing. Most hyped longevity molecules (Resveratrol, Fisetin, Fucoidan) fail upon rigorous scrutiny (ITP replication or human dose-equivalency). The only “Strong” tier interventions are those with massive human clinical datasets (Creatine, Omega-3, Vitamin D). The host introduces a critical distinction between therapeutic biologic candidates (SS-31) and consumer supplements, warning that “research grade” peptides carry unacceptable safety risks for healthy users. The new “gold standard” for personal protocols is biomarker-guided optimization (measuring blood levels) rather than blind supplementation.

Key Pivot: A notable shift in stance on Lithium Orotate, now elevated to “Strong/Good” based on a 2025 Nature paper (Yankner Lab) linking depletion to Alzheimer’s, despite the host’s general conservatism.

II. Insight Bullets

  • The “Anti-Aging” Label is a Red Flag: Any product explicitly marketed as “anti-aging” or using “proprietary blends” is immediately categorized as “Avoid” due to likely under-dosing and opacity.
  • Creatine is Non-Negotiable: Ranked #1. The benefits for body composition and potential neuroprotection (3-5g/day) outweigh all other supplements. Doses >5g (20g “loading”) are dismissed as influencer fad without long-term evidence.
  • Omega-3 & Vitamin D Require Testing: Blind supplementation is discouraged. The protocol is “Test, Supplement, Retest” to reach specific biological targets (Omega Index >8%; Vit D 40-60 ng/dL).
  • Resveratrol is Dead: Categorically dismissed as the “most overhyped intervention ever.” Zero effect on lifespan in reliable meta-analyses; yeast data was flawed.
  • SS-31 (Elamipretide) is Not a Supplement: It is a prescription drug with FDA accelerated approval (Sept 2025) for Barth Syndrome only. Use in healthy adults is “Red Zone” due to injection risks, unknown purity, and potential to disrupt mitochondrial homeostasis.
  • Fucoidan’s “Mouse Trap”: While a 2025 preprint shows lifespan extension in mice via SIRT6, the human equivalent dose (approx. 50g/day) renders it practically impossible. Sourcing purity is a major safety hazard (heavy metals).
  • NAD+ Bioavailability Gap: NAD+ precursors (NR/NMN) remain in the “Promising but Overhyped” limbo. Tissue-specific decline is not universal; indiscriminate boosting may not be necessary for all.
  • Urolithin A is the “Rich Man’s” Bet: Ranked “Promising” for mitophagy. Reproducible mouse data and early human signals for muscle function, but effect size is likely small compared to exercise.
  • Fisetin Failed: Despite senolytic hype, mouse lifespan data is not reproducible. Human data is weak.
  • Lithium Orotate (Microdose): The sleeper hit of the list. 10mg/day (elemental approx.) is supported by strong epidemiology (suicide/dementia reduction) and new 2025 mechanistic data on Alzheimer’s protection.
  • CoQ10 is Niche: Useful for statin intolerance or heart failure, but useless for general longevity in healthy adults.
  • Fatty 15 (C15:0): Marketing currently outpaces science. Categorized as “Overhyped” pending human clinical trials, despite “essential fatty acid” claims.

III. Adversarial Claims & Evidence Table

Claim from Video Scientific Reality (Current Data) Evidence Grade Verdict
SS-31 (Elamipretide): Recently granted FDA accelerated approval. Accurate. FDA granted accelerated approval for Barth Syndrome in Sept 2025 based on intermediate endpoints (muscle strength). FDA.gov 2025 Level A/B (Disease Specific) Verified (Context: Disease only)
Lithium Orotate: Protects against Alzheimer’s; depleted in AD brains (Yankner, Nature 2025). Accurate. 2025 study confirmed lithium sequestered in amyloid plaques; low-dose rescue in mice. NIH/Nature 2025 Level D (Mechanistic/Mouse) + Level C (Human Epi) Plausible / Experimental
Fucoidan: Extends lifespan in mice via SIRT6 (Gorbunova Lab). Accurate. March 2025 preprint shows ~13% extension in males. Mechanism: SIRT6 deacetylation & mADPr. BioRxiv 2025 Level D (Pre-clinical/Mouse) Translational Gap (Dose: ~50g HED)
Resveratrol: Failed to extend lifespan in rigorous testing (ITP). Accurate. NIA Interventions Testing Program (ITP) found no lifespan benefit. 100+ studies meta-analysis confirms no effect. Level A (Meta-analysis) Strong Support (for “Ineffective”)
Fisetin: Senolytic effects not reproducible in mouse lifespan. Accurate. Recent ITP data and independent replications have failed to show robust lifespan extension, contradicting earlier hype. Level D (Failed Replication) Speculative / Overhyped
Urolithin A: Improves mitochondrial health/muscle function. Supported. Human trials (MitoIMMUNE, 2024/2025) show improved immune/muscle markers. ASCO 2024 Level B (Small RCTs) Promising
Fatty 15 (C15:0): Essential for longevity; “Geroprotector”. Contested. Evidence largely driven by Venn-Watson (founder). Independent human RCTs for longevity endpoints are lacking. Level E (Commercial/Expert Opinion) Overhyped

IV. Actionable Protocol (Prioritized)

High Confidence Tier (The “Daily Drivers”)

  • Creatine Monohydrate: 3–5g daily. Dissolved in water/shake.

  • Target: Cognitive support + Muscular hypertrophy.

  • Condition: Must be paired with resistance training.

  • Omega-3 (EPA/DHA): Dose titrated to blood test results.

  • Target: Omega-3 Index > 8%.

  • Starting Ref: ~1300mg EPA+DHA daily (Variable).

  • Vitamin D3: Dose titrated to blood test results.

  • Target: Serum 25(OH)D levels between 40–60 ng/mL.

  • Note: Requires ~3 months to stabilize levels before re-testing.

Experimental Tier (High Upside, Low Risk)

  • Lithium Orotate: 5–10mg daily (elemental lithium).

  • Rationale: Neuroprotection/Alzheimer’s risk reduction.

  • Safety: Doses are <1/10th of psychiatric prescription levels.

  • Urolithin A: 500–1000mg daily.

  • Rationale: Mitophagy support for older adults unable to achieve high-intensity exercise volume.

  • Cost/Benefit: Low efficiency per dollar compared to fasting/exercise.

Red Flag Zone (Avoid)

  • SS-31 (Elamipretide): Do not use unless diagnosing a mitochondrial disease (e.g., Barth Syndrome). Injection site risks + unknown long-term impact on healthy mitochondria.
  • Proprietary “Anti-Aging” Blends: 100% rejection rate.
  • Resveratrol: Discontinue use. Waste of capital.
  • Fucoidan: Avoid until purified, dense sources are validated (current effective dose is physically impossible).

V. Technical Mechanism Breakdown

1. SIRT6 Dual-Activation (Fucoidan Mechanism)

The 2025 Gorbunova paper identifies Fucoidan not just as an activator of SIRT6 Deacetylase (chromatin stabilization), but also SIRT6 mono-ADP-ribosylation (mADPr).

  • Relevance: mADPr activity is notably higher in centenarians. It represses LINE1 retrotransposons (parasitic “jumping genes” that destabilize the genome with age).
  • The Catch: The molecule is a massive sulfated polysaccharide with poor bioavailability, requiring massive intake to achieve nuclear activation in humans.

2. Cardiolipin Remodeling (SS-31 Mechanism)

SS-31 is a tetrapeptide that selectively targets the Inner Mitochondrial Membrane (IMM).

  • Action: It binds to Cardiolipin, a phospholipid crucial for the curvature of mitochondrial cristae (folds).
  • Effect: By stabilizing Cardiolipin, it optimizes the Electron Transport Chain (ETC) supercomplexes, reducing electron leak (ROS) and improving ATP efficiency.
  • Risk: In healthy mitochondria with normal Cardiolipin, adding an exogenous peptide stabilizer may disrupt natural dynamic remodeling (fission/fusion).

3. Mitophagy Induction (Urolithin A)

  • Pathway: Urolithin A induces the degradation of damaged mitochondria (Mitophagy) by preventing the accumulation of PINK1/Parkin on the outer membrane of defective organelles, signaling them for lysosomal destruction.
  • Outcome: Clears “metabolic garbage,” allowing the cell to repopulate with fresh, efficient mitochondria (Biogenesis).
3 Likes
#131

I just watched the episode. Matt is fairly conservative (he threw shade at my beloved ss-31-How rude! :slight_smile: so I took note he takes 10mg of lithium per day vs a more conservative dose. This definitely gave me pause.

I have been recommending my family take 1mg, so I might rethink this.

I personally take 6mg per day, but I’m on an SGLT2 which supposedly cuts the effective dose in half-ish… I assume Matt is in the same boat.

It makes me wonder if I should take more, or more importantly, if I should have my family take 5mg (they are not on sglt2’s).

What are most here doing??

#132

Yes - but you also have to keep in mind he’s now running a longevity clinic that has to follow the laws quite strictly. And I suspect he wants anything he says in the podcast to mirror anything he’s going to tell people in his clinic. He’s not going to be selling / supplying grey market peptides to anyone (I would bet), so he’s also not going to promoting them on YouTube. And Matt also knows that most o the non-GLP1 peptides people are using are gray market, which have lots of issues/risks as we’ve discussed - so generally he’s going to recommend most people avoid them (as I think is appropriate right now).

And for SS-31, despite its been in clinical testing for a decade or two, its only been approved by the FDA last year, and he’d have to follow the regular drug supply chain in the USA… and I just looked up prices for the brand name SS-31 (Forzinity). So this is a peptide that Matt is unlikely ever to offer in his clinic, no matter what the evidence.

Unit Approx. List Price (WAC) Notes
Per Vial ~$15,000 Each vial contains 280 mg (3.5 mL).
Per Month ~$60,000 Requires 4 vials for a 28-day supply.
Per Year ~$780,000 – $800,000 Based on continuous daily dosing.

So, it doesn’t make any sense for him to put too much time or effort into it, at a high level. I suspect he hasn’t gone into the biology in depth.

2 Likes
#133

Those are excellent points! You’d take it out of my cold dead hands, but he had me doubting myself!

In the video, he pointed out it was fast tracked through the FDA so we don’t have all the normal safety data.

I don’t know if it made the AI summary, but in the video he noted Hazel worked with his mentor

And WHOA those prices!!!

1 Like
#134

I had not viewed the video and not much was in the summary - so I want back and listened to the section on SS-31 peptides and though it was interesting and more helpful than just the summary in this area.

Matt obviously knows quite a bit about the SS-31 peptides, given that his mentor was someone who worked closely with Hazel on the early research on SS-31 in mice many years ago. Matt brings up good points… there is no indication that SS-31 will have any impact on lifespan. He does admit that if the mouse studies translate to humans, we could expect some benefits in bio-energetics (muscle energy) and frailty reduction. He then balances that agains the risks of grey market peptides. And it’s true we don’t know the long term effects in humans (but thats going to be the case with most newer peptides or drugs given the relatively short phase three clinical studies).

The counter is that there actually have been quite a few human clinical trials with SS-31 with no side effects seen other than the injection site pain. The key issue in the equation (for me) is the safety/purity issue of the SS-31 peptide you’re using. If it’s well tested and quality verified, then the risk is only in the peptide itself (not the contaminants, etc. that could be in the peptide). And given the results seen so far, I would still be interested in trying it.

Here is the full transcript of the section where Matt discusses the SS-31 peptide. I think its worth a read, for anyone interested in this peptide:

Transcript Segment: SS Peptides (SS-31/Elamipretide)

Matt Kaeberlein:

SS peptides I’m going to put in the “avoid” category unless you have mitochondrial disease. I don’t think there’s any evidence in healthy people. And by the way, that’s not a supplement. That’s a prescription medication. So that’s the one that I was saying doesn’t really fit into the supplement category.

I know a lot of people are excited about peptides in general. A lot of people are excited about SS peptides. I say avoid. And I feel pretty strong on the avoid here. Again, not because I know anything dangerous about SS peptides, but I think there’s a few reasons not to go out and start taking SS peptides from a purely risk-reward perspective, unless you have some sort of mitochondrial disorder, and then that’s a different conversation.

So, just to make sure everybody really understands what we’re talking about here, SS peptides are in fact not a supplement. They are sort of a prescription medication, and they land in this gray area where doctors can prescribe them. As we’ll talk about, the SS peptide most people are going to be taking is SS-31 (or Elamipretide) that was just recently granted accelerated FDA approval. So a doctor can now prescribe SS-31, but it falls in this gray area of the peptides where some people are getting them from compounding, some people are getting research grade off the internet. It’s just kind of ugly and messy right now.

So what do we know about SS peptides from a data perspective? They’ve been around for 20-plus years. SS-31 in particular. I actually was around a lot of the early SS peptide work at the University of Washington because Hazel Szeto, one of the “S’s” in SS, collaborated extensively with my mentor, Peter Rabinovitch, on SS-31 work looking at mitochondrial function in mice. Peter, by the way, is one of the greatest people who I’ve ever had the opportunity to work with. As I said, he was a mentor of mine, and I’m just super grateful for all of the support he gave me throughout the years. Also a fantastic scientist.

And they did a lot of work in mice, treating mice with SS-31 and looking at: where does it go? How does it work? What are the effects on health span and lifespan? And so I think what we’ve learned through Peter’s studies and lots of other studies that Hazel did is SS-31 indeed localizes to mitochondria. It can interact with cardiolipin at least in some contexts. It can reduce mitochondrial fragmentation, reduce reactive oxygen species production, and increase ATP production or energy production. But the idea that SS-31 or any of the SS peptides are general “mitochondrial boosters” supporting mitochondrial function is just sort of a massive oversimplification of the biology. It’s very context dependent.

And my recollection of the mouse data that Peter’s lab and others did was that SS peptides can sort of remodel the mitochondrial proteome, improve some aspects of mitochondrial energetics, potentially improve muscle function in aging mice, but didn’t increase lifespan. So again, it’s one of these situations where maybe a few health span metrics are improved, but it doesn’t seem to be, at least in those experiments, a general longevity drug or general geroprotector. Having said that, if it had similar effects in people without any side effects, that might be something to consider. Maybe it would be beneficial for frailty in people as they’re aging.

So what do we actually know though about SS peptides in people? So, as I mentioned, Elamipretide was recently approved by the FDA—that’s SS-31—for Barth syndrome. But it wasn’t a sort of full approval. It was this accelerated approval path. And that’s because Barth syndrome is a rare childhood mitochondrial disorder where there really aren’t any other treatments available. So, it got this accelerated approval based on the fact that it’s for a severe disease without any alternative treatments, and there was a reasonable expectation that it might work.

So what hasn’t been shown is that SS-31 actually has efficacy for Barth syndrome or for anything else, at least not in the context of an FDA approval process. So we don’t know—it’s gotten this accelerated approval. We don’t know whether it actually works for this indication or for any indication for that matter. There are some other ongoing studies in humans and I think we just have to kind of wait and see. And I know a lot of people are frustrated with the FDA clinical trial process. It takes too long. I get all that. And you really want to know what the safety profile looks like and whether there’s a reasonable expectation that this is going to work for what you want to use it for.

Nonetheless, a lot of so-called “self-proclaimed longevity doctors” have started prescribing SS-31 for use in their patients. And you know, I’m sure they’re starting to get case reports, information about whether SS-31 has benefits, what the side effects look like, but it’s really hard to know what’s real and what’s not real at this point.

So, for that reason, I’d say the reward part is pretty questionable. Like maybe modest benefits for mitochondrial function. There was one study that I’m aware of in healthy older people where there were some indications of improved mitochondrial bioenergetics. That’s kind of what we know I think for healthy older people in SS-31 at this point. So that’s the potential reward. Maybe modest impact on mitochondrial function, maybe best case scenario, modest protection against frailty maybe, but not a lot of indications this is going to be a big effect size intervention. Certainly not compared to something like exercise.

And then what is the risk? Again, we really don’t know because we don’t have, as far as I know, any long-term studies in people. And there’s a few reasons to think that there could be some risks. First of all, we don’t really know the dosing for what we’re trying to use it for. Again, not a lot of data in people, and most of that comes from mitochondrial disease. So, we don’t know the dose. We know we are putting a foreign peptide into mitochondria. And so anybody who understands mitochondrial biology will recognize that there are some reasons to think you want to be careful about putting something into mitochondria that isn’t normally there. Doesn’t mean it’s going to have detrimental effects. Doesn’t mean it’s going to cause problems, but often it is the case when you put foreign proteins or peptides into the mitochondria, it creates a stress response that can be net detrimental. So we want to be a little bit careful about that.

And then I think outside of the SS peptide itself, and this is true for a lot of the peptides that are out there in general, there’s real reasons to be careful about purity and contamination in the peptide preps themselves. For reasons that somewhat due to lack of regulation, somewhat due to opportunism by people of questionable ethics, you might say there’s a lot of people selling peptides of uncertain purity. And so if you get it from a compounding pharmacy, that’s better than buying it from a random person on the internet who’s selling research grade peptides. But even peptides from compounding pharmacies have been sometimes found to have impurities that can lead to problems like allergic reactions.

So, I think you just want to be real careful when you think about the risk-reward with peptides in general, especially peptides that are not FDA approved, especially peptides that are research grade, and with peptides that we don’t have a ton of data, especially human data like SS-31 to understand what the safety profile looks like. I feel pretty good about putting SS-31 and SS peptides in general in the avoid category for now. They are super interesting, super promising biologics. I’d just like to see a bit more data.

2 Likes
Hazel Szeto, SS-31 peptide, the World's First FDA-Approved Mitochondria-targeted Drug (Longevity Summit, 2025)
Hazel Szeto, SS-31 peptide, the World's First FDA-Approved Mitochondria-targeted Drug (Longevity Summit, 2025)
#135

Before you worry about how to get legitimate uncontaminated SS-31, you first have to ask why you’d want to. I looked at the evidence, and similar to Matt, I just don’t see it. First and foremost, let’s keep in mind that there is no evidence whatsoever that SS-31 is a longevity molecule - in fact, in mice it has failed (to extend lifespan). So, if it’s not a longevity molecule, perhaps it’s a healthspan molecule? Well, we have some results in mice mitochondria and the like, but it’s pretty equivocal insofar as you have to make a lot of assumptions that what it’s doing to the mitochondria is health promoting for people who don’t have mitochondrial disease. Even the FDA approval was an emergency one, where they’re willing to lower the standards simply because there is no other intervention and this at least has some hints it might work for a rare disease condition - but we’ve had little clinical experience here, and it may very well fail in even that once it is more widely used for its indication.

That leaves “healthy” people. As Matt has pointed out - there is no evidence whatsoever that SS-31 does anything in healthy people mitochondria that somehow enhances the mitochondria or represents a helpful kind of mitophagy. I mean, no disrespect to Hazel, but apart from prolific mechanistic speculation, there is no hard outcomes data in humans.

So you’re asking me to invest time and effort and twist myself into a pretzel to take a “possible” healthspan extender? Do you know how many interventions exist that can make a much better healthspan claim than SS-31 - you’d quickly lose count.

Meanwhile, worry about purity and dosing. There’s the SS-31 thread, where there’s literally a handful of posts about any possible evidence of benefits and the rest is worrying about how to score the right stuff and dose and adminstration routes and all that stuff around it. And I keep coming back to “bbbb bbbb bbut why take it in the first place, can we get back to that?”

I’m not saying you or anyone should not take a chance on SS-31 (or any other molecule), but you frequently reference ROI in time, money, effort and opportunity cost. And looking at the evidence, this ROI strikes me as absolutely abysmal. Based on the evidence - clear evidence - not vibes, authority, influencer or scientist personal enthusiasm, but cold hard evidence - I just don’t see this gamble, I wouldn’t bother staking 1 penny on this peptide. There’s a universe of other molecules out there that I’d sooner invest in. And quite frankly, I’m trying to - if anything - prune my stack. Adding this makes no sense - to me, but it might be very persuasive to you, because we all have our own situations to evaluate, which is why I rarely make unqualified blanket statements that a molecule is “good” or “bad”, because we all have our own profiles. However, I think it’s always useful to turn on a skeptical light with any drug, to make us evaluate again whether it really makes sense. Even with stuff that we already take. And so, I follow the rapamycin literature, because who knows, maybe one day evidence will turn up that makes me drop the rapamycin gamble. I try to do this with all my drugs and supplements. I regularly ask myself - does this drug still have a place in my stack? That goes triple for a prospective drug, an addition to the stack, like SS-31. For me - not saying for you or anyone else! - SS-31 is not even in the ballpark, city, world, solar system, galaxy. Of course, as usual YMMV.

2 Likes
#136

You heard about lithium orotate almost 4 years ago from Rapamycin News. So it was not a hidden sleeper for us. The observational data at the time was was very promising.

Stay tuned to Rapamycin News for the latest in healthspan and lifespan interventions. No other website is even close if you want to be an early adopter. Sorry Mike, Attia, Huberman, et al. You impart only a fraction of the information published on this site. And, the information here is freely shared.

6 Likes
#137

Most days I take 5 mg lithiumorotate. Some days I up the dose to 10 mg.

2 Likes