#1

YouTube video

4 Likes
#2

Would be nice if you could summarize it in 2-3 sentences. Wish I had time to watch videos. So what’s the real reason?

8 Likes
#3

My TLDR; investors need to invest in human trials based based on multiplee pre-clinical labs results. Rapa got a shout out among others.

Appeciate that doesn’t tell you about the others, but the video is digestable. Listen on fast forward

#4
1 Like
#5

I have run this through Claude. 15 mins is a short video and I have watched a bit. I quite like Brad Stanfield even if I disagree with him on a number of things. He does try to operate on an ethical manner.

I’ll create a tidy transcript, summary, and critique of this talk on longevity investments.

TIDY TRANSCRIPT

Title: Stop Burning Your Capital - How to Get Outsized Longevity Return on Your Investment

Introduction

The speaker discusses four medication classes showing promise in longevity (two currently prescribed in clinic), skincare devices for reversing aging signs, and importantly, two major mistakes in the longevity field to avoid.

Part 1: Two Cautionary Tales

Resveratrol Failure

  • Early 2000s: Heralded as longevity supplement
  • Claimed to activate SIRT1/SIRT2 enzymes
  • Based on single-cell research and mouse studies
  • GSK purchased rights for $720 million
  • After years of attempts and millions more spent, research could not be replicated
  • Total loss of investment

Ovarian Stem Cell Failure (OvaScience)

  • Promise: Using stem cells to treat infertility and extend fertility window
  • Company founded in 2011 based on initial lab findings
  • Could never replicate initial results
  • Led to investor lawsuit and SEC fraud settlement
  • Company eventually collapsed after mergers/acquisitions

Common Pattern:

  1. Exciting initial discovery (usually single lab)
  2. Massive investment flows in
  3. Years later: inability to replicate results
  4. Total loss and credibility damage to longevity field

Part 2: The Better Approach - Learning from SpaceX

SpaceX Falcon 9 Analogy:

  • Goal: Reusable rockets (launch and land)
  • Built from solid foundation based on testing
  • Failures were expected and used for learning
  • Iterative approach led to 2015 success

Key Lesson: Build from solid scientific foundation, then scale.

Part 3: The Interventions Testing Program (ITP)

What Makes ITP Special:

  • Tests molecules in mice for health/lifespan extension
  • Same experiment run simultaneously in three different labs
  • Uses genetically diverse mice (better human translation)
  • Built-in reproducibility

Why This Matters:

  • Cancer research example: Amgen (2012) tried replicating 53 foundational cancer studies
  • Only 6 of 53 were reproducible
  • Explains disappointing cancer treatment progress

ITP Saved Capital - Two Examples:

  1. Fisetin (Senolytic)

    • Theory: Remove senescent cells to prevent tissue damage
    • ITP result: No lifespan extension, no benefits
    • Conclusion: Senolytic preclinical work not ready for scaling

  2. Nicotinamide Riboside (NAD+ precursor)

    • Theory: Support NAD metabolism central to cellular function
    • ITP result: No lifespan extension, no benefits
    • Human trials: Mixed results, nothing significant
    • Conclusion: Pre-clinical NAD work insufficient

Part 4: Four Promising Medication Classes

1. SGLT2 Inhibitors (Currently prescribing)

  • Mechanism: Kidneys excrete glucose
  • Primary use: Type 2 diabetes
  • Repurposed benefits:
    • Heart failure: Reduced hospitalization and cardiovascular death (non-diabetic patients)
    • Kidney disease: Less protein leakage, slower decline, reduced dialysis risk
  • Pre-clinical evidence: May help with senescence and glucose spike management
  • ITP result: Canagliflozin extended male mice lifespan by 14%
  • Future potential: Low-dose use in healthy individuals

2. Rapamycin (Currently prescribing)

  • “Golden child” of ITP
  • Extends male and female mice lifespan 17-25%
  • Challenges: Used clinically as immunosuppressant (transplant patients)
  • Recent progress: Correct dosing shows no immunosuppressive effects or increased infections
  • Speaker’s research: Clinical trial combining rapamycin with exercise in older adults
  • Results submitted for peer review (available after talk)

3. GLP-1 Medications (Currently prescribing)

  • Primary use: Type 2 diabetes
  • Mechanism causes significant weight loss
  • Repurposed for: Weight loss, sleep apnea, heart failure, kidney health
  • Potential: Micro-dosing in healthy individuals for longevity
  • Innovation pipeline:
    • GLP-1 alone
    • Tirzepatide (GLP-1 + GIP): Greater weight loss
    • Retatrutide (triple combination): Even greater weight loss (Phase 2)

4. PCSK9 Inhibitors

  • Mechanism: Lower LDL cholesterol by increasing liver LDL receptors
  • Potential: Revolutionize cardiovascular disease prevention
  • Innovation: Small interfering RNA (siRNA) versions
    • Single dose reduces LDL by ~50% for 6 months
    • Massively improves adherence
    • Could dramatically reduce cardiovascular disease

Part 5: Skin Aging Reversal Devices

Traditional Approach:

  • Ablative lasers: Burn top skin layer, stimulate repair
  • Great results but significant recovery time

Modern Innovations:

  • Non-ablative devices: Nearly as effective, minimal recovery
  • LED/red light therapy
  • IPL (Intense Pulsed Light): Treats freckles and age spots
  • Speaker personally uses and recommends to patients

Conclusion: The New Investment Model

Old Model: Bet big on early results

New Model:

  1. Validate initial results (reproducibility)
  2. Iterate and learn
  3. Scale from solid foundation

Benefits:

  • Avoid hype traps
  • Invest in validated interventions
  • Protect capital
  • Build credibility for longevity field

SUMMARY

This talk presents a framework for longevity investment decisions based on scientific rigor. The speaker warns against two major failures (resveratrol and OvaScience) that cost hundreds of millions due to irreproducible initial findings. The solution: the Interventions Testing Program (ITP), which tests interventions across three labs simultaneously using genetically diverse mice, ensuring reproducibility before human trials.

Four medication classes show promise: SGLT2 inhibitors (14% lifespan extension in mice, already prescribed for diabetes/heart/kidney disease); rapamycin (17-25% lifespan extension in mice, new dosing protocols avoid immunosuppression); GLP-1 medications (weight loss and metabolic benefits, newer combinations show greater effects); and PCSK9 inhibitors (particularly siRNA versions offering 6-month LDL reduction from single dose).

The core message: validate science through reproducible pre-clinical work before massive investment, avoiding the hype cycle that has damaged the field’s credibility.

CRITIQUE

Strengths:

  1. Compelling framework: The SpaceX analogy effectively illustrates iterative, evidence-based development vs. premature scaling.

  2. Concrete examples: The resveratrol and OvaScience failures provide sobering context, while the Amgen cancer replication crisis (6/53 studies) powerfully demonstrates systemic reproducibility problems.

  3. ITP emphasis: Highlighting a rigorous, multi-site testing program is valuable and underutilized in longevity discourse.

  4. Balanced approach: Acknowledging fisetin and NR failures prevents selective reporting and builds credibility.

  5. Practical relevance: Speaker actively prescribes these medications, suggesting real-world clinical experience.

Weaknesses:

  1. Mouse-to-human translation oversimplified: While ITP uses genetically diverse mice, the speaker doesn’t adequately address the fundamental limitations of mouse models. Mice aren’t simply “small humans” - they have different metabolic rates, lifespans, and disease mechanisms. The 14% canagliflozin extension in male mice (notably, not females) is presented optimistically without discussing why sex differences matter or what this might mean for humans.

  2. Rapamycin data withholding: Teasing “really interesting” results while keeping them confidential undermines the talk’s transparency theme. If results are under peer review, basic findings could still be shared. This creates the same “exciting discovery” hype the talk warns against.

  3. Off-label prescribing concerns: The speaker “routinely prescribes” these medications but doesn’t clarify whether this is on-label (diabetes, heart failure, kidney disease) or off-label (healthy individuals for longevity). If off-label, ethical considerations about prescribing medications with known side effects to healthy people deserve discussion.

  4. GLP-1 uncritical presentation: GLP-1 medications have significant side effects (nausea, vomiting, potential pancreatitis, and concerning emerging data about muscle loss with rapid weight loss). “Micro-dosing in healthy individuals” is speculative and potentially dangerous without acknowledging these risks.

  5. PCSK9 cost barrier ignored: These medications currently cost $5,000-14,000 annually. The siRNA versions will likely be expensive too. This is a massive barrier to the “revolutionary” cardiovascular disease prevention claimed.

  6. Skin devices tangential: The skincare segment feels disconnected from the medication focus and lacks the same evidence standard. “Non-ablative devices offer almost as good results” - compared to what studies? This section undermines the evidence-based message.

  7. Financial conflicts unaddressed: As someone prescribing these medications and involved in rapamycin trials, the speaker likely has financial interests (speaking fees, research grants, potentially consulting). These should be disclosed.

  8. Selective ITP interpretation: The speaker uses negative ITP results (fisetin, NR) to dismiss those interventions but positive results (canagliflozin) to enthusiastically endorse SGLT2 inhibitors. However, one 14% male-only extension might be a fluke - where’s the ITP replication data for canagliflozin? The same skepticism applied to fisetin should apply here.

  9. Missing nuance on existing uses: SGLT2 inhibitors and GLP-1s are already prescribed for their approved indications. Framing these as “longevity interventions” when they’re treating diseases (diabetes, heart failure, obesity) conflates disease treatment with lifespan extension in healthy people - a critical distinction.

  10. Validation paradox: The talk advocates validating through ITP before human trials, yet three of four medication classes highlighted are already in human use for other conditions. This isn’t following the proposed framework - it’s repurposing existing drugs, which is a different strategy entirely.

Bottom Line:

This is an engaging talk with important messages about reproducibility, but it doesn’t fully practice what it preaches. The speaker advocates skepticism and solid evidence yet promotes interventions (particularly rapamycin and “micro-dosing” GLP-1 in healthy people) that haven’t completed the validation process they champion. The framework is sound, but the application is inconsistent. A stronger version would include confidence intervals, effect sizes, side effect profiles, cost analyses, and disclosed conflicts of interest.

7 Likes
#6

Good talk, and well balanced considering the short length. I think some of the critiques above are fair, but some are not. The cost of PCSK9i isn’t Brad’s fault, and the ethics discussion isn’t really relevant here if the doctor and patient both consent.

The GLP1RAs really seem great, the more I learn about them. As somebody who doesn’t need to lose weight, I’m still curious about experimenting with one, likely at the lowest dose. I know lots of people taking them now, and nothing bu positive reports.

4 Likes
#7

Thank you John for the summary! Will ask my doc if SGLT2 in a low dose could benefit my kidney.

2 Likes
#8

In the beginning I was a huge fan of Dr. Stanfield. But lately he seems to be succumbing to internet fame and all that entails.

1 Like
#9

Summary under Rapamyacin says

" * Recent progress: Correct dosing shows no immunosuppressive effects or increased infections"

Does he tell us what the “Correct dosing” is?

1 Like
#10

The problem is that we know that rapamycin can cause increased infections when taken for mTOR inhibition purposes. The complex question is how much mTOR inhibition we should be aiming for. I am perhaps on the extreme of high and infrequent.

I do think Brad Stanfield is generally good, but I am not sure his rapamycin trial will produce a lot more than PEARL (which concluded that if you don’t take a lot of rapamycin not a lot happens - which we already knew).

5 Likes
#11

Well they did find some things, even though they messed up the dosing:

“Further, we have discovered since the conclusion of this trial that compounded rapamycin is approximately 3.5x less bioavailable than commercially available formulations, suggesting that the 5mg and 10mg rapamycin groups received an average equivalent of 1.4mg and 2.9mg respectively”

4 Likes
#12

I think that was probably already known which is why rapamycin has normally got a coating. They may have discovered this from their own perspective, but the fact was known because that is why the pills are coated.

4 Likes
#13

You are correct.

#14

I would suggest encapsulating it in delayed-release capsules from Amazon.
image
Extended Release - Protects ingredients from stomach acids. Our size 00 empty vegetarian capsules delayed release empty vegetarian capsules have unique properties that slow down capsule break down after swallowing.
Each veg capsule is made from 100 percent HPMC vegetable cellulose and will dissolve in your gastrointestinal tract for maximum absorption of your supplement ingredients.

Because of the tariff fiasco, I have been taking maximum measures to extend my effective supply of rapamycin.
I can put three 1 mg tablets in each size 00 capsule. So, my current routine is ruby red GFJ, delayed-release capsules, plus EVOO. I have no idea how this is actually working because I don’t measure the results.

2 Likes
#15

Relaxed Meatball: re “nothing but positive results”:

N=1 here, but on very very low dose of Rybelsus I went from about 104 to 95 pounds in a couple of weeks (not what I had intended), felt awful, developed severe back pain which a CT scan showed to have been a gall stone and also probably a small kidney stone. That’s what you get if you lose weight too quickly and the liver can’t quite deal with it.

5 Likes
#16

Yikes! I’m sorry you went through that. My wife (around 115lbs) is experimenting with a very lose dose of Wegovy and seems to be fine. It’s reduced her appetite, but she hasn’t lost any weight. But the person who prescribed it was pretty reluctant to do so in somebody with such a low body weight to begin with.

1 Like
#17

Same here… and I increasingly found errors in his logic and sometimes unjustified conclusions. So, I pretty much stopped paying attention to him.