178. Dr. Matt Kaeberlein: The Science, Risk, and Hype Behind Today's Longevity Trends

Summary

Podcast Summary

Podcast: Extend Podcast with Darshan Shah, MD
Episode: 178 – Dr. Matt Kaeberlein: The Science, Risk, and Hype Behind Today’s Longevity Trends
Air Date: July 2, 2026
Guest: Dr. Matt Kaeberlein (Professor, longevity researcher, host of The Drive podcast, member of the ITP Steering Committee)
Host: Dr. Darshan Shah, MD

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Episode Overview

This episode explores the rapidly evolving field of longevity medicine, cutting through the hype and false promises to examine the real science behind today’s most popular longevity interventions. Dr. Matt Kaeberlein, a leading researcher in aging biology, joins Dr. Darshan Shah to discuss the evidence, risks, and gray areas around current trends such as peptides, rapamycin, SGLT2 inhibitors, and more. Together, they advocate for rigorous, evidence-based thinking and separate marketing fantasy from scientifically validated therapies, emphasizing the need for cautious risk–benefit analysis as longevity therapeutics move into the mainstream.

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Key Discussion Points & Insights

1. The Current Longevity Landscape: Science vs. Hype

• Both experts lament that marketing often outpaces the science in the longevity field, leading to misinformation and sometimes dangerous practices ([02:22]).
  • Quote: “So much of it feels like marketing has got ahead of the science…Some of the less evidence-based talk can be dangerous.” – Dr. Kaeberlein [02:22]
• They stress the importance of probabilistic thinking (evaluating likelihood, confidence, and personal context) rather than falling for binary (yes/no) answers ([03:37]).
  • Quote: “Very little in science or medicine is 100% rock solid...helping people try to figure out, for this particular supplement, in my situation, where do I fall – is it a 90% or a 5%?” – Dr. Kaeberlein [04:37]

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2. Risk Assessment in Longevity Interventions

• Risks associated with pharmaceuticals are often scrutinized, but unapproved anti-aging interventions (like peptides) are assumed risk-free simply due to lack of published harms ([05:19], [08:17]).
  • “In the absence of evidence of risk or harm, there is no harm. [But] people...completely dismiss what could go wrong.” – Dr. Kaeberlein [05:19]
• Proper risk assessment is hampered by underreporting of side effects, lack of large-scale clinical trials, and poor manufacturing practices, especially for unregulated peptides ([08:17], [21:20]).
  • Memorable Moment: Discussion of DNP, a historic “exercise mimetic” that killed hundreds before gaining FDA oversight, used as a cautionary tale for current peptide trends ([11:13]).
  • Quote: “Hopefully we won’t end up with another situation like dinitrophenol where a bunch of people die…So it would be nice if we could just land somewhere in the middle.” – Dr. Kaeberlein [12:31]

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3. The Need for Rigorous Clinical Trials

• Dr. Kaeberlein strongly advocates for randomized, placebo-controlled clinical trials for top unregulated peptides, citing both feasibility and cost-effectiveness relative to current research expenditures ([12:34], [16:42]).
  • Quote: "It would be really easy to get the clinical trial data on the top 10 prescribed unregulated peptides…this is easy, it’s doable, and we’ll know the answer.” – Dr. Kaeberlein [12:34]
• They discuss the practicalities of sample sizes (e.g., 1,000 participants for safety data) and highlight government or philanthropic funding as key since pharma is uninterested in non-patentable molecules ([14:41], [17:43]).
• The issue with “research grade” peptides sold online is addressed, including major safety and quality concerns. Lab testing sometimes finds not only the wrong peptide but unrelated or dangerous compounds ([21:19]).
  • “Sometimes it's a completely different peptide or sometimes it’s another compound, like even MDMA in there.” – Dr. Shah [21:19]

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4. Relative Efficacy: Peptides vs. Other Longevity Drugs

• Most non-FDA-approved peptides, though biologically active, show weaker effects and greater risks compared to drugs like GLP-1 receptor agonists (GLPs) or SGLT2 inhibitors ([22:45]).
  • “None of [the popular peptides] are going to move the needle as much as the GLPs. The GLPs are great drugs...I’m not aware of any of the other peptides...where there’s any evidence they’re anywhere near as effective.” – Dr. Kaeberlein [22:45]
• Risk–reward analysis should favor established drugs or proven methods whenever possible.

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5. Peptide Approval & the Role of Pharma

• The hosts clarify the difference between patentable peptides (like GLP-1s, due to novel formulation and pharma investment) and other peptides that can’t attract pharma due to expired or non-existent patent protection ([24:45]).
• Discussion of possible regulatory pathways such as conditional approval (used commonly in veterinary medicine), with suggestions to pilot similar systems for human aging interventions ([28:18]).
  • Quote: “If we overweight safety…there is a rationale for having a strategy like [conditional approval] in humans…Show safety, we’re confident that it’s safe enough, and then you create some structure where people can have informed consent around this.” – Dr. Kaeberlein [28:18]

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6. The Interventions Testing Program (ITP)

• Dr. Kaeberlein describes the ITP, a National Institutes of Health initiative rigorously testing nominated drugs/supplements for lifespan effects in genetically diverse mice across three independent labs, making it the gold standard for preclinical longevity data ([33:10], [35:37]).
  • Quote: “The built-in triplicate replication…gives you a high degree of confidence this is a real signal.” – Dr. Kaeberlein [36:37]

Key Findings:

• Rapamycin: Strongest, most robust longevity effect; 15% increased lifespan when started late in life in mice, with dose being more important than age at start ([41:00]).
• Other hits: Acarbose (anti-diabetic), estrogens, and SGLT2 inhibitors—drugs with both lifespan and healthspan effects. Signals from ITP tend to align with positive real-world human data, e.g., UK Biobank studies ([44:29], [45:41]).

Timestamps:

• [40:56] – Accidental delayed administration of rapamycin leads to major discoveries about starting interventions later in life.
• [46:00] – On SGLT2 inhibitors and estrogens; metformin and NAD boosters show little/no benefit in mouse or human data.

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7. Healthspan vs. Lifespan: Measuring and Interpreting Outcomes

• Interventions that robustly increase lifespan in mice nearly always confer healthspan benefits. The reverse isn’t always true, and the hosts caution against extrapolating results from poorly conducted studies ([47:30], [48:53]).
• NAD boosters: Questionable evidence base in both mice and humans, with inconsistent effects and overhyped mechanisms ([51:12]).

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8. Biomarkers and the Challenge of Human Application

• Epigenetic clocks show promise in research but are noisy, lack error bounds, and have unproven clinical utility ([55:47]).
  • Quote: “There is no difference that’s big enough between two measurements that you can statistically be confident it’s a real difference.” – Dr. Kaeberlein [56:00]
• Traditional blood-based or functional metrics remain most reliable for now.

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9. The Dog Aging Project: Bridging Preclinical and Clinical Research

• Dr. Kaeberlein details the large-scale, NIH-funded clinical trial testing rapamycin in 580 companion dogs, with endpoints including lifespan, echocardiography, neurological function, and molecular signatures ([57:49]).
  • Quote: "If we’re successful at improving health and longevity of people’s dogs, there’s intrinsic value to that. Dogs also age very much like people do...but they do it seven to ten times faster." – Dr. Kaeberlein [59:08]
• Makes translational research feasible by leveraging rapid canine aging for shorter studies.

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10. Rapamycin Off-Label Use and Human Application

• The safety profile of rapamycin at lower doses (used for longevity, not transplantation) appears reasonable, with mouth sores being the most common minor side effect ([66:55]).
  • “I think rapamycin is one of the few cases for off-label use...where we have reasonable evidence across multiple age-related domains.” – Dr. Kaeberlein [66:55]
• Rapamycin and SGLT2 inhibitors are currently Dr. Kaeberlein’s top candidates for evidence-based, off-label use for healthy lifespan extension in people.
  • "If you forced me to...make a guess, I’d say yeah, rapamycin and SGLT2 inhibitors probably slow biological aging in people.” [66:55]
• Cautions that definitive proof in humans is still pending, and encourages individual risk–benefit analysis.

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11. The Future of Longevity Medicine

• Both agree: rigorous, evidence-driven, proactive prevention is moving into the mainstream, with more clinicians engaging the conversation ([71:09], [72:31]).
  • Quote: “For as much as I get frustrated with the big name people who aren’t very scientific, I think they have helped the discussion...There does seem to be a shift in mentality...towards recognizing that proactive health is what we should be doing.” – Dr. Kaeberlein [71:09]
• AI, better study design, and systemic improvements in regulatory science may soon accelerate translation.
• Optimism for a near future where the average person could achieve 10–20 more healthy years through evidence-based interventions.

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Notable Quotes & Moments

• Probabilistic Thinking:
  • “Very little in science…is 100% rock solid.” – Dr. Kaeberlein [04:37]
• Marketing vs. Science:
  • “People selling these things will tell you it’s all 100%.” – Dr. Shah [04:56]
• Risk Underestimation:
  • “That’s why we need the randomized placebo-controlled clinical trials…” – Dr. Kaeberlein [08:17]
• Efficacy Reality Check:
  • “None of [the peptides] are game changers like the GLPs are.” – Dr. Kaeberlein [22:45]
• Dog Aging Project Mission:
  • “From that moment, I felt like I had to really do this...We could slow aging in dogs.” – Dr. Kaeberlein [61:07]
• Translational Optimism:
  • “AI will help...There is a lot of reason to be excited [about proactive health].” – Dr. Kaeberlein [71:09–72:22]

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Timestamps for Key Segments

| Time | Topic/Highlight | |-----------|-------------------------------------------------------------------| | 02:22 | Marketing vs. Science in Longevity | | 05:19 | Probabilistic Thinking; Risk–Reward Assessment | | 08:17 | Risk Underreporting of Peptides | | 11:13 | DNP Cautionary Tale | | 12:34 | The Need (and Feasibility) of Clinical Trials | | 16:42 | Who Should Fund These Trials? | | 21:19 | Peptide Mislabeling and Contamination | | 22:45 | Peptide Efficacy vs. GLPs | | 28:18 | Conditional Approval Pathways | | 33:10 | ITP Structure and Rationale | | 40:56 | Rapamycin's Paradigm-Shifting Discovery | | 45:41 | ITP Hits—Acarbose, Estrogens, SGLT2 Inhibitors | | 47:30 | Lifespan vs. Healthspan in Mice | | 55:47 | Biomarkers & Epigenetic Clocks | | 57:49 | The Dog Aging Project | | 66:55 | Rapamycin & SGLT2 in Human Application | | 71:09 | The Future: Proactive, Rigorous, Accessible Longevity Medicine |

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Takeaways & Final Thoughts

• Be Skeptical of Longevity Hype: Demand large, well-controlled human data, especially for new and unregulated interventions.
• Risk–Reward Analysis Is Crucial: Both for new compounds’ efficacy and the very real possibility of catastrophic outcomes.
• Science Is Moving Forward: Animal models like the ITP in mice and the Dog Aging Project are bridging preclinical data toward meaningful human applications.
• On the Horizon: Safer adaptation of drugs like rapamycin and SGLT2 inhibitors, more rigorous clinical trials, potential regulatory innovations, and a move toward proactive, personalized longevity care for everyone.

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Social Links:

• Dr. Matt Kaeberlein: Instagram, X (Twitter), LinkedIn, and YouTube (Kaberlien)

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Recommended for Listeners Who:

• Want to understand the real state of longevity research
• Seek clarity on peptides, rapamycin, SGLT2 inhibitors, or biomarkers
• Value skeptical, evidence-driven health advice over marketing claims
• Are clinicians or proactive individuals aiming to navigate the wild west of longevity medicine responsibly

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End of Summary

Transcript

[A]

Before we get started with this episode, I'd like to invite all of you to the first ever next Health Longevity Summit happening in Nashville, Tennessee at the Conrad Hotel on Saturday, September 12, 2026. This is an all day summit where you're going to be hearing from some of the best speakers in longevity medicine, including Dr. Vonda Wright, Dr. Luisa Nicola, many of the podcast guests that you've heard here on the Extend podcast. And of course I'm going to be there curating the entire day. We also have incredible vendors coming so that you can try the latest technologies in health, wellness and longevity. Go to next-health.com summit and buy your ticket today. We only have 400 spots and they're going quickly. That's next health.com summit. I look forward to seeing you all there. Welcome to extend with me, Dr. Darshan Shah, a podcast dedicated to cutting edge science research, tools and protocols designed to help you extend your health. Having become one of the youngest doctors in the country at the age of 21 and trained and board certified at the Mayo Clinic, I've accumulated three decades of practice as a board certified surgeon and longevity expert. Over that time, I've discovered that a mere 20% of health knowledge yields 80% of the results. When it comes to your health span, we are living in a new era where we are creating a new health care system no longer focused on disease management, but achieving optimal health and vitality. Join me as I interview world renowned experts offering you a step by step guide to proactively avoid disease and most important importantly, extend your health span. Dr. Matt Kaeberlin, thank you so much for joining the podcast Extend. It's been a long time that I've been following your work and watching your YouTubes and listening to you and it's just such an honor to have you. Thank you for being here.

[B]

Thank you. Yeah, no, it's a pleasure to be able to join you and I'm just glad we were able to hammer it out here in beautiful Miami.

[A]

I know we made it happen. I was like, if you're coming, I'm going to make this happen. So thank you for carving a few hours out for me. And you know, I followed your work for a long time and really appreciate what you're doing to really advance the science, but also bring to this crazy exploding term longevity, some sensibility too, you know. And so I really appreciate your scientific view of really talking about what is working, what's coming and bringing truth to this.

[B]

Well, thank you. And I do try. I mean, I'm a scientist by training. So that's the lens that I look at the world through. And I think, you know, as you alluded to, the space is growing so rapidly and so much of it feels like marketing has got ahead of the science that, you know, I think it's important for those of us who are scientifically and evidence minded to really try to set expectations because there's a lot of reasons to be really excited about where we're at now and what's coming. And so I think I want to give people a realistic sense of where we're at instead of, you know, some of the less evidence based talk that's out there right now. And honestly, some of the less evidence based talk can be dangerous. And so also helping people to be able to navigate the space, avoid getting into trouble, separate the signal from the noise.

[A]

Yeah, it's so important right now. And this is where, you know, we've kind of leaned into this podcast of just making sure that we not have the people that talk about this from more of a marketing perspective and really just talk about the science. Right. And so I think you're right. The marketing does get way ahead of the science because there's obviously a lot of money to be made. You know, in history, how many people have made money off of selling, you know, the, the longevity cure or the fountain of youth.

[B]

Right, yeah, no, absolutely true. And you know, I think again, there is a place for that and the consumers demand it. Right. The reason there's money to be made is because people want some of this stuff. But I think, you know, there are a lot of people who, they want the new solutions, but they also want to know what's real. And there's a lot of gray area where, you know, this is, I think, something that's hard for maybe people who aren't trained in science or statistics to appreciate. There are things that we feel really confident about. Right. And that's kind of where I tend to try to live. But then there's this whole gray area of things that, you know, there's some evidence, some reason to believe there's value or reality. There's. But our confidence is a lot lower and Maybe it's a 10% chance that's going to work. And so really trying to help people understand that kind of probabilistic thinking about data because very little in science or medicine is 100% rock solid. It's somewhere between 99% confidence to 1% confidence and helping people try to figure out where for this particular supplement, in my situation, where do I Fall, is it a 90% or a 5%? And then you can make your decision. So I think that's just an important framework for maybe people to spend more time thinking about.

[A]

Yeah, absolutely.

[B]

Because the people selling these things will tell you it's all 100%.

[A]

Right, right, right. Yeah. The reality is usually it's a bell shaped curve or some sort of like statistical distribution, how anything works for you. Right? That's right. You have to really understand like your own biology and combine the data, the knowledge of the data with your knowledge of yourself and see what's going to work for you. Right, Yeah.

[B]

I think the other piece there that a lot of people tend to underestimate is the really trying to do an accurate risk assessment. Right. So we're talking about the reward part, right. How likely is this to work and if it does, how big is the benefit going to be? There's that piece. Those are two things you should think about on the reward side. But then there's the risk side. And I think, you know, it's kind of interesting to me because a lot of people, when you talk about pharmaceutical drugs, right, Big pharma, bad word. Nobody likes big pharma. Everybody is scared of the risk of the side effects. Right. But you get outside of that world. I'll just put peptides out there. And peptides is a big category. There are some peptides that are great, there are some peptides that are FDA approved, there are some that aren't. It's all over the place. But in that category, people seem to default to. In the absence of evidence of risk or harm, there is no harm. It just completely dismiss what could go wrong. And so I think that's where it's also important just to try to get people to understand, what do we know? What do we know? And based on that, what can we really estimate the actual risk is? And then within risk, it's really important to consider there's risk of something minor bad happening. Then there's the risk of catastrophic side effects where you get a stroke or you get cataracts or you die. So even if the absolute risk of a catastrophic outcome is pretty low, you really should ask yourself, is it worth it to me to maybe lose a little bit of weight if there's a 0.1% chance that I'm gonna have a stroke and be paralyzed for the rest of my life? I think people don't really think about that in a rational way. We get very irrational, it seems like in wellness. So I started, I sort of started referring to this as the wellness blinders, like we put blinders on about the risk some people do in the wellness space. And I just think it's really important for people to really think hard, you know, what's the best outcome that could happen? How likely is that to happen? And what's the worst outcome that could happen? And how likely is that to happen? And then you can sort of make an informed decision. Now what I just said I think makes sense. And I recognize it's really hard for the average person to be able to do that calculation because they don't have access to all the information. They don't necessarily have the ability to dive into the primary literature. Understand, okay, there was this one study that was done in mice, but nobody's ever tested this in humans. What does that mean? So they need to rely on hopefully reliable medical professionals to guide them in that decision.

[A]

Yeah, and the other aspect of risk too is risk is just really underreported. Like if you go looking for, we'll use a peptide example, right? Complications of BPC157, for example, it takes a lot for someone to see a complication, then write about it as a case report, put in the literature. That process usually doesn't happen very, very often or frequently. And so my problem with risk is too is we really just don't know without the studies as well, where someone's very mindfully documenting the side effects that are happening on a certain group of people. Right.

[B]

I think that's super important. And again, this is where, you know, maybe the average person doesn't fully appreciate what you just said because they're going to. Some people will say, yeah, but BPC157 has been by functional medicine doctors for 20 years. Right. If it was really bad, we would know already. What you just said, I think is really important. That would be true if we got reports for everybody who's using it accurately about who benefited and who was harmed. This is why we need the randomized placebo controlled clinical trials where we're going to get both the efficacy signal if it's there and the safety signal if it's there, and be able to say in this group of optimally 1000 plus people, this many people had side effects in the BPC157 group, this many people had side effects in the placebo group. It was or wasn't different. Right. You're not going to get that from individual doctors who are prescribing it, you know, one off to their patients. And also, even if the doctors wanted to be honest and report side effects. There's no place for them to really do it in a rigorous way. And that's only if the patients tell them so. Again, in the context of a randomized clinical trial, people are going to be surveyed about any side effects that they get. We'll be able to capture that data. Outside of that, we just miss it. Right. And so I think that's. Maybe most people don't realize this, but it's only a tiny handful of the peptides that are being prescribed outside of the FDA approved peptides, the unapproved peptides. It's only a tiny handful that we have any real human data on at least randomized clinical trial human data. I think right now there are two clinical trials for BPC157 happening. I don't think any have been published. So, you know, at the highest quality level, we have no data on safety for BPC157 and that's one that's been used, you know, for a long time. You get into the newer shiny object peptides that are out there now and like we just have no data at all. I've been shocked. And it goes beyond peptides. There are a bunch of doctors using, or you can buy it on the Internet, small molecules. They aren't even peptides. They're kind of labeled as peptides. They're not peptides. Where there's no human data and doctors are prescribing it, people are selling it, people are taking it again. I've actually got an episode coming out on my podcast now. I don't know if you know the story of dinitrophenol, but I think this is a really interesting, you know, example of what can, can go wrong. And I'm not suggesting anything out there now is as dangerous as dinitrophenol, but it's a really interesting example of a drug that was a metabolic activator. I'm sure you've heard that term that today it would probably be called an exercise mimetic, right? Or a mitochondrial activator that kills people. Once you get outside a very narrow range, it's really effective at causing weight loss because it uncouples the mitochondria, causes you to just burn ATP. The problem is when you do that, you give off heat and if your body temperature gets too high, bad things happen. Right? So we don't know how many people did, it's in the hundreds died from DNP between 1920 and today. It's not really used anymore today because it was just prescribed outside of Any sort of FDA regulatory oversight. And it's actually DNP is actually one of the major catalysts for the current FDA regulations. I think it's 1938 Food, Drug and Cosmetic Act. So I think we're starting to see a shift. And so this is interesting, right, because that 1938 act, I think was the pendulum swaying towards more regulation. Right. For drugs. FDA could say a drug's not safe. It had to go through clinical trials and be approved to be allowed to be prescribed. And we're seeing a pendulum swing back the other direction. And look, I personally am very libertarian when it comes to health. I think if people are fully informed, they should be able to make their own decisions about what they do with their body. It's that fully informed piece that is really hard. But we're seeing this shift back now away from regulation where people and medical professionals, some feel much more comfortable prescribing and using therapies that don't have randomized clinical trial data. Hopefully we won't end up with another situation like dinitrophenol where a bunch of people die from this. If we do, I think we'll see the pendulum swing back the other direction. So it would be nice if we could just land somewhere in the middle.

[A]

Somewhere in the middle.

[B]

I know I've been talking for a while, but.

[A]

No, this is great.

[B]

But I've got one thing that I, that really, you know, I feel strongly about, and it's quite frustrating to me, is that it would be really easy to get the clinical trial data on the top 10 prescribed unregulated peptides.

[A]

Exactly right.

[B]

This is not. This is a solvable problem that actually doesn't cost that much money compared to the what we spend on, you know, what I would call low quality research through nih. This would be a drop in the bucket. We could actually get answers. We get a committee of experts together say these are the 10 things we need to test and go test them. That's easily doable. And then we would know, do they work, who do they work for and what do the risks look like. So somebody ought to just in leadership in this country or in some other country, just get it together, do these clinical trials. This is easy, it's doable, and we'll know the answer.

[A]

Yeah, and I wonder this all the time myself, like, why are the trials not being done? You know, we always say, like, it's so expensive to do a trial in the United States. Right. The FDA makes it extremely expensive to get something through the drug for a pay for Approval, but we're not talking about getting it approved as a drug. We're talking about doing a clinical trial to, to your point, get to safety and efficacy data.

[B]

Right.

[A]

And then at least we know that this thing is not harming people.

[B]

That's right.

[A]

Right. So, yeah, and so I do, I do think. And what would like the sample size be for a trial like that?

[B]

I mean, well, it depends a little bit on the question you want to ask. Right. So usually the way you determine the a size for a clinical trial is you're going to look at whatever the end point is that you're interested in. So if it's, you know, kidney disease or a certain type of cancer, whatever, and there are statistical tools you can use to say we need this large of a cohort in order to be able to detect this big of a change. So it's going to depend on what the indication is. If we're really only interested in safety, like, you could make the decision, you know, efficacy is important, but what we're really concerned about is safety. If we were really interested in safety, then I think what you would need to do is say in the general pop population, if that's who this study is going to be done on, let's just say people 55 and older.

[A]

Right.

[B]

What is the likelihood within that population that people are going to develop? And then you have a long list of different conditions and then you do the statistics. Again, I don't know what the answer is. I haven't tried to do the math. Yeah, I'm guessing a thousand people would be enough to see at least a strong safety signal. And again, like, I'm not suggesting this is going to be dirt cheap, but I think you could, if you designed this in an efficient way, you could do this at 50 million per intervention. You test 10 interventions, that's, that's 500 million. I mean, that's a lot of money. But again, compared to what we spend on research that doesn't give us any good information, at the end of the day, this would be quite valuable and maybe it would be a lot cheaper. Like, maybe I'm off by fivefold even. But. So I think it's a matter of what's the benefit that would accrue from spending that much money. And I think in this case it's a pretty big benefit. And I would love to see. I mean, we were chatting briefly before we started filming about the mouse interventions testing program. This could be a human version of that, right? Where every year the government just says, we're Going to fund five clinical trials for interesting drugs that pharma isn't going to move forward for whatever reason. We have a committee of experts, I would suggest both medical and scientific experts that convene, maybe evaluate a longer list, pick the five that are going to go through testing, and then test them. That, to me, would be an amazing program that would provide a lot of really valuable information and hopefully would help people who want access to these new therapies feel more confident and doctors feel more confident in using them and knowing who is going to benefit from these things.

[A]

Yeah. When I read about the ITP program, which I heard about through you, actually, and your work that you put out there, I was like, why are we not doing this for humans? This seems like the way forward for these molecules that the, that pharma is not interested in. Right. I mean, it really. And like you said, like, it's. It might seem like a big number, but we spend so much more money on so many other things that go nowhere, you know, and so.

[B]

Yeah, and once you get outside of biomedical research, I mean, we could go down the path of all the stuff we spend money on that goes nowhere. So. But I do think, you know, what you said is important because. Because we're talking here primarily about things that pharma either has abandoned or won't pursue because they don't have patent protection. So when this conversation comes up, a lot of times people will get very upset and they're like, well, why should the government pay for, you know, what pharma should pay for? And I understand that. I understand that perspective. What we're talking about here are therapeutics that pharma is never going to do the clinical trials for, either because they don't have patent protection or because they're maybe already FDA approved for something else. And so there's no incentive for them to do the very expensive clinical trials for FDA approval or label expansion. So it requires. Either they don't get done, which is where we've been, you know, for the last 50 years, or the government's going to have to fund these things, or private philanthropy is going to have to fund these things.

[A]

Right. And I think right now, with a massive interest in peptide, I mean, there's companies making millions and they're not even FDA approved yet. Like, there needs to be some sort of meeting of the minds here where people are putting money into some sort of research program like this where the safety and the efficacy, because that's just going to benefit even those companies that are selling the peptides. Right, yeah.

[B]

Although there is another piece here that's worth mentioning which is that most of the companies making money off of peptides now are doing it outside of even the quality manufacturing regulatory piece. Right. And they label it as research use only or not for human consumption. So that's, that's another. If you're considering using these peptides, that's another safety consideration you need to take into account is if you buy it over the Internet as opposed to say getting it from a prescription at a compounding pharmacy, if you buy it off the Internet and it says research use only, you really have no idea about the manufacturing quality of that product. Is it even what you think it is? And if it is, what else is in there? So that's the other piece. I think that right now is very problematic because there are a lot of, I'm just going to say bad actors out there who are selling research grade peptides and other molecules on the Internet outside of the regulatory environment. Everybody knows, I mean they put research grade on there, everybody knows people are going to put these things in their bodies and we don't have any insight into product quality. So now these, now what you see now are these secondary markets pop up where people can get their peptide they bought off the Internet tested by somebody else to tell them if it's really what they want it to be.

[A]

It's so crazy right now it's such a topsy turvy world. And I think in July, you know, when some of these peptides go back on the FDA regulatory list, my hope is that a lot of these research grade things have to go away.

[B]

It'll be interesting to see. So I don't think they'll go away unless there's enforcement because it'll still be cheaper. So, so, and you know, just for people who may not know exactly what you're referring to, I think it was, I don't know how many years ago it was. It wasn't that long ago several of these peptides were put onto a list and were no longer allowed to be compounded by compounding pharmacies. That I think is going to change. I don't think it has changed yet, but every indication is that that will change back to where compounding pharmacies can now compound these peptides when a doctor prescribes them. So that gives more quality control around the composition of the final product because these compounding pharmacies are required to manufacture and compound at a certain level of quality. Having said that, I think the research grade market will still be less Expensive than the compounded versions. And a lot of people will just go to grab, you know, they'll just go to the lowest cost product that's out there, maybe not realizing there is this difference in terms of potential quality of the product. So I think really the only way that's going to go, go away is if there's some sort of enforcement that cracks down on the people who are selling these things on the Internet.

[A]

It seems like there's signals that there will be enforcement because, you know, peptide scientists, which is one of the largest of these research grade peptides, close their doors and they, they just stopped operating. Because my hypothesis there from people I talked to is because of the signals in the market that things are going towards these becoming more regulated. So my hope is that does happen because you know, to your point, like some of these research grade peptides that get tested, a lot of them, the testing not only shows that they do not have any of the peptide in there, sometimes it's, it's because I know some of these people that own these labs. Yeah. And they tell me like sometimes it's a completely different peptide or sometimes it's another compound like even MDMA in there.

[B]

Wow.

[A]

Yeah. And so people are injecting themselves with compounds that they have no idea that could have severe side effects.

[B]

Right.

[A]

And so this is where the research grade ones are potentially or likely, you know, they're just very dangerous. Right. And so at least the compounding pharmacy, to your point, not only their manufacturing guards, like to make sure there's not like infectious organisms in there, but there's also quality and also certificate of analysis requirements.

[B]

Right?

[A]

That's right. So yeah, yeah, yeah.

[B]

I mean, again, you know, and I want to suggest that everybody who's selling peptides on the Internet is a bad actor. I mean, there are people who are trying to do it. Well, I still think personally I would not go into that line of business, but you know, we'll leave that on the table. But the problem is there's so many actors out there, there's just no way for the average consumer to, to know like who's really trying hard to manufacture this properly, who's, you know, cutting and who's putting other stuff in there that's not even the right active ingredient. The other piece though that I think, you know, unfortunately because of sort of the influencer craze around peptides that a lot of people have been misled into believing that these are gonna be life changing therapies. Right. So look, the common peptides, again, the eight or 10 that we're talking about. They're biologically active, they do have biological activity. For some people, they can have beneficial effects. Again, that's a generalization. We could talk about the specific peptides, but none of them are game changers like the GLPs are.

[A]

Right.

[B]

And I think it's just important for people to appreciate that none of them are gonna move the needle as much as the GLPs. The GLPs are great drugs. They've got some issues if not used properly with the proper education around lifestyle, but they work. I'm not aware of any of the other peptides that people are excited about where there's any evidence they're anywhere near as effective as the GLPs at what they're supposed to do. So I think it's just important for people to realize when you do this risk reward analysis, on the reward side, the reward is lower, I would say, than it's going to be for a glp. And the risk is way higher when we add on the lack of human safety data, the questions around manufacturing and sourcing. So you really have to consider what analysis leads you to believe that this is the right thing to do. And it may be. Again, I'm not going to suggest that if you've done a careful risk reward analysis and you think that this is the right path for you, that you shouldn't do it. But I do think, at least for me, it's hard to justify that particular path. Especially when we've got other tools like the GLPs or lifestyle modifications that can achieve the same goals, or hormone therapy. Right. I think that can be done much more safely than some of these peptides that are, at least in principle, are supposed to increase growth hormone or reduce visceral adipose.

[A]

Right, right, right.

[B]

We have better, more tested and more effective strategies to do that.

[A]

And because they are made in pharma, the GLPs, I mean, when you get it, it is what it says in the bottle.

[B]

Assuming you don't buy research grade terzepatite. Yeah, right.

[A]

Can you break down for us just to kind of complete this conversation? Because it's such a great conversation that we just happened into. And then I'll take us back to the conversation we were going to have, but I just want you to break down for the audience here why, you know, GLP1s are peptides. They were also used by functional medicine way before the pharma industry were able to patent and sell them.

[B]

Right.

[A]

Why are these patentable versus other peptides?

[B]

So it really Depends on the peptide. So in order for pharma to be able to get the IP around a peptide that they're going to want to move it through the FDA clinical trial pipeline, it's going to have to be a new molecule that they have developed or that they buy from someone else that wasn't patented more than 20 years ago, because there's a certain patent life on a new molecule. So a lot of these peptides that we're Talking about now, BPC157 and others, some of them actually came up through pharma and they were abandoned. So they were abandoned because they didn't have the efficacy signal.

[A]

Right.

[B]

So. And so far, no other pharma company is going to pick up something that a different pharma company got through phase 2s, didn't see efficacy and abandoned. Right. And then some of them have just been around for so long that there's no new patent life available.

[A]

Got it.

[B]

To make it worth moving it through the FDA process. And again, you know, that's a different conversation. You know, is the FDA process too slow, too expensive, too burdensome? Yeah, I think everybody would say, yeah, it is. What I don't see are a lot of people coming up with solutions to that. And so I think that's a different conversation around how do we change the way that new therapeutics are evaluated? Definitely it can be done more effectively, more efficiently, for a lot less money. Again, the incentive structures, though, right now it's actually pharma kind of likes the system. They complain about it, they kind of like it because they've got a monopoly on huge motor because nobody else can afford to move things through the full FDA approval process in humans. And I'll just throw something out. I haven't really thought this through carefully. So there may be good reasons why this wouldn't work. But as a template, there is a faster path in companion animals. So a lot of people don't realize this, but there's a center for veterinary medicine that approves drugs for dogs and cats and pets. And they use something called the conditional approval pathway fairly commonly there, if any people are familiar with the company, loyal. They're trying to move a drug through this pathway for longevity in dogs, which you could never do in humans for lifespan, for obvious reasons, it takes too long. But this is a pathway where you have to show safety. And if you can show safety and make a case. But it's more of a scientific and bureaucratic case for efficacy than it is doing the pivotal clinical trials. But make a case, there's a pretty good chance this is gonna work. And we've already shown it's safe. You can get what's called conditional approval, which allows the company to bring it to market. They've got five years to do the full safe, the full efficacy studies and actually prove efficacy. So this goes a little bit back to what we were talking about before. If we overweight safety in this safety efficacy equation, which I think a lot of people would find reasonable, there is a rationale for having a strategy like that in humans, particularly for things that are harder to really show. Clinical trial signal for now, if it's a severe form of cancer and all you have to do is show that people are going to live a few weeks longer, maybe that's not right for the conditional approval pathway. But if it's an endpoint where it's going to take a year or two years and a large population to see the efficacy signal, maybe there's a reasonable case there for a conditional approval. You show safety, we're confident that it's safe enough, and then you create some structure where people can have informed consent around this that they know, okay, it may or may not actually work, but we're pretty confident that it's safe. And so it's up to you whether you want to try this. I really like that idea.

[A]

That's a great idea.

[B]

And so the question is, how do you actually implement that in humans? But again, I think we can look at the companion animals and that could be a template for doing something like this in humans. There is a conditional approval like pathway in humans, but it's very rarely used. And I don't really understand the bureaucracy around why it's not more widely used.

[A]

So I mean, and that's, that's such a great point, by the way, because I thought the conditional approval pathway was something that the FDA could use, but it's only for animals.

[B]

Well, again, there is something like that in humans, but it's very rarely used. And I don't know, there's got to be some legislative or bureaucratic reason why it's not more commonly used. I believe we're going back to peptides that the SS31 peptide, the mitochondrial peptide, I think it's elamipretide, got something like a conditional approval for a rare childhood mitochondrial disorder where they, because they'd done other clinical trials, so they had a pretty good dossier of safety and they weren't able to show efficacy yet. But FDA gave them this conditional approval. And I don't know the exact path they took to get there. But again, maybe that can be expanded in some way to make it easier.

[A]

Yeah, I mean, this is such a great conversation because in the next five, 10 years I feel like we're going to figure this all out because I'm glad you're optimistic. There's a massive interest in peptides right now and it's almost like this balloon that's about to pop. And so something's going to have to happen. Either they get completely taken off the market again or there's going to be some sort of either a conditional proof pathway or some type of ITP like program or something. And at least the safety data, like that's such a critical piece of this.

[B]

I definitely hope it's, it's the latter and I would love to see both of those things happen. I mean, I think they're both, you know, real steps towards solving problems that a lot of people would benefit from. That there's, I don't think there's a, any good reason to object to doing that. I mean, I suppose you could object to the human ITP program because it costs money, but again, when you look at the benefit that would accrue from spending that money compared to other stuff we spend money on, like this is a no brainer.

[A]

Right.

[B]

So hopefully that happens again. My only fear is that if we start to see, you know, a lot of catastrophic negative effects popping up, that there's going to be a, you know, a pushback pretty soon. Yeah. So hopefully that doesn't happen. And again, I don't really think any of the, the commonly used peptides now are all that dangerous. It's more the manufacturing and impurities piece that I'm concerned about. You're probably familiar with what happened at Radfest last year where two women were getting peptide injections and ended up in the hospital. And it was in the vendor hall at the conference. That kind of behavior, especially when there are outcomes like that, I think puts the entire field at risk. I was just at my first Hollywood longevity party and they were giving out intranasal peptides at the party. And I'm just like, seriously, come on, guys. But you know, the flip side of that is it's probably better than what people were snorting in the 1980s in Hollywood. So yeah, it's all relative.

[A]

Oh my gosh. Yeah, this is, you know, in stories like this, it makes it the wild West. It doesn't have to be like, you know, the people injecting peptides with no workup or anything in the vendor hall of A conference like that did not need to happen.

[B]

Right.

[A]

And it just brought a tremendous spotlight to the potential dangers here, which just sets everything back quite a bit, unfortunately.

[B]

That's why we can't have nice things.

[A]

Yeah, exactly. So I'm 52 right now, but I'm still pushing all of my limits. I'm running long distances, I travel across many time zones to support my work, and I just want to live my life to the fullest. Staying active as I age isn't just about willpower. It's about supporting my mitochondria, the powerhouses of my cells, with the energy that they need to to recharge my muscles and recharge my brain. Mitopure is a supplement that I take. It's backed by solid research showing that it can boost cellular energy, increase muscle strength, and support overall healthy aging. Personally, I take Mitopure every single day. It's helped me continue my active lifestyle, whether it's a high intensity workout or keeping up with my kids. So if you are looking to support your body and want to feel younger from the inside out, my friends at Timeline are offering you a 10% discount on your first order. Go to timeline.comdrshaw to get started. That's timeline.com D R S H A H. Your future self will thank you. You know, going back to this ITP program, which is just so interesting to me, you're on the steering committee and it kind of really addresses this gray, gray area of molecules, I think, really well, at least as a first step. Right?

[B]

Yeah.

[A]

And so I'd love for you just to tell the audience what is this program and kind of the structure around it.

[B]

Sure, yeah. So the itp, or interventions Testing program was started, I think back in like 2005 with the idea that the field needed some way to rigorously test small molecules primarily, but interventions in general in mice for effects on lifespan. And it was a explicit decision at the time to really only focus on lifespan. And the rationale behind that is that you can improve health in one domain or a couple of domains during aging, but if you're really slowing biological aging, you should be able to increase the population lifespan by some significant amount. So that's what's measured. And so the idea was we would nominate or we would allow the community to nominate small molecules to be tested. Anybody in the scientific medical community, in fact, anybody in the general public can submit a nomination. This happens every year, and depending on how much funding is available, somewhere between five and seven interventions will be selected. So there are two committees that select these interventions. An access committee, which is a larger committee, more like a traditional NIH review, three reviewers each, give it a score. And then there's the steering committee, which is what I've been on now for about 15 years, that makes the final decision on which molecules get selected. And so a lot of really interesting stuff has come out of this program over the years. A couple other things that might just be worth mentioning for people who really want to understand a little bit more is another explicit decision that was made early on was to use what's called a four way cross, it's called UMHET three as the strain designation. And the reason for this is.

[A]

These are the mice.

[B]

Yeah, these are the mice. The genetic background of the mice. Most mice in laboratory studies are inbred mice. So C57 Black6 is the most common strain. And so they don't have much genetic diversity. But of course people and animals in the real world are genetically diverse. So this mouse strain, um, HET3 is designed to have a lot more genetic diversity than the typical mouse strains. I don't know how important that is. It's, it's a, it's a reasonable thing to do. I don't know how much it matters, but that's the way all of the studies have been done in this, um3 background. So probably the most famous result to come out of the ITP was very early on. So in the first set of six or seven drugs that they tested was.

[A]

I'm so sorry, I'm going to interrupt you one more second. And just so people really understand this ITP process is that there's also two laboratories doing three laboratories.

[B]

I should have said that. Right. So that's another structural feature that's really unique and I think important here. So from the very beginning there have been three sites where every intervention is tested in replicate. One is at the University of Michigan. Rich Miller has been the director of that site for the entire time of the interventions testing program. Another is at University of Texas Health Science Center, San Antonio. Randy Strong is the director of that site. And then the third is at Jackson Labs in Bar Harbor, Maine. David Harrison was the first director of that site. And so, yeah, so that triplicate replication is important because when they get the data back, they do analyses at each individual site and then also pool all of the data. And obviously you feel a lot more confident about a result when it works at each individual site as opposed to if it, if you only see a significant effect when you pool the data,

[A]

does that answer the question of like, is this study able to be replicated? Well, yes. Now you've replicated the same study in three different locations.

[B]

I believe it's about as good as you could do in a program like this.

[A]

Yeah, I agree. I thought that was important to mention. Just because the data coming out of the ITP is some of the best signals you can get around this particular type of data.

[B]

It's definitely the gold standard for longevity data. And by longevity I mean lifespan data in mice. And it's important to say, you know, the field has been led astray multiple times by one off studies where somebody reported, you know, that a drug increased lifespan in mice and then when people tried to replicate it, it didn't work. In fact, the ITP has failed to replicate, you know, a few of the more popular drugs that are out there. And just to name names, let's name Resveratrol, nicotinamide, riboside are two of the big ones. NR of course, is an NAD booster that lots of people are still really excited about. Sorry, didn't replicate even in mice. And if you look at those studies, the NR study is sort of, I think, illustrative of, of what can often go wrong. So in these one off studies where somebody reports a lifespan extension, so you will often, if you look at the actual data, you will see that the control animals in that study were short lived. And what the intervention did was it just brought them back towards more where their lifespan should have been. That's a classic sign of a poorly conducted mouse lifespan study. I am very skeptical of any one off study that has short control lifespans and somebody claims a lifespan extension because they almost never reproduce. So I know we're getting in the weeds a little bit, but this is, I mean, it's important to understand that one paper is not something that you want to hang your hat on, especially when we're talking about something in the longevity space. That's why replication is so important. So yeah, that built in triplicate replication, while not perfect, again, if you see a signal at all three sites, that gives you a high degree of confidence this is a real signal. And I will say it's been frustrating at times for, I know, for the ITP investigators and for those of us who have a vested interest in the itp, sometimes it doesn't work at all three sites. And so then you're kind of left with what does that mean? And so it is a bit challenging, but that's the nature of science. That's why we repeat experiments. So anyways, I think the ITP Showed its value very early on, because in that first set of drugs, there were five or six. They were started in either 2004 or 2005 was rapamycin. And there's an interesting story here about how sometimes, you know, you can have really, really happy accidents in science. So because of the way the ITP works, they gotta have a really large group of mice. I mean, we're talking, you know, 100, 100 mice in each group at each site, times five to seven drugs. So it's a large cohort of animals you've gotta breed up, right? They don't just magically appear. So when they were starting this first set of drugs, they realized that the rapamycin wasn't bioavailable in the formulation that they had. And this is well known in human medicine. Rapamycin is unstable at gastric ph, so you have to do something to it. You have to put a coating on it to get it to the small intestine where it's absorbed. But they had to start the experiment because they had thousands of mice ready to go. So they were like, well, crap, we'll just work on an enteric coating and we'll start the mice on the rapamycin. When we get it done, it'll probably only take a couple of months. So they started all the mice on the other drugs at either six or nine months of age, which is maybe 30 years old for a human, maybe less. And it ended up taking them, I don't know, 12 months to figure out the enteric coating. So the rapamycin mice didn't actually start getting the drug until they were 20 months old. But it was an accident that wasn't designed, and nobody thought it was gonna work. At that time. The field believed you could only get big effects on lifespan if you started the treatment at young age, because nobody had found anything that broke that pattern. And fortunately, what they found was that rapamycin gave a pretty large effect. I mean, again, in mice, a 15% increase in lifespan. There aren't that many things that reproducibly have that magnitude effect on lifespan. So rapamycin had a 15% increase in lifespan in females, a 9% increase in males, starting at 20 months of age. And that really, I think, was a paradigm shift that got people. And again, that's important because if you're thinking that we might want to try rapamycin or whatever drug comes out of the ITP in people, you don't want something you gotta start giving to teenagers, right?

[A]

Absolutely.

[B]

You want something, you can start giving to people in their 50s, 60s, 70s, 80s.

[A]

Right, right.

[B]

So it was a paradigm shift in the way the field thought about longevity therapeutics that it was actually possible to have meaningful effects on aging trajectories. Starting an intervention in middle age. And now people have gone back. Rapamycin now is the most robust and reproducible intervention in mice for longevity and health span. Dozens of labs have shown the same thing. The interventions testing program has shown at higher doses, you get bigger effects.

[A]

So. And what about a young. Has anyone tested it at a younger age as well?

[B]

Yeah, it doesn't seem to really make much difference. So this is another thing that's been surprising. Dose has a bigger effect on magnitude of lifespan extension than when you start, it seems. Now, again, I have to be a little careful and say nobody has done all the different possible, you know, combinations. Right. And you have to appreciate we're always going to be working with insufficient data when it comes to lifespan experiments because they're so long, so expensive. But with what we've got, I think we can say with some degree of confidence that you get a much, much bigger range of lifespan extension by changing the dose than changing whether you start at six months or nine months.

[A]

Got it.

[B]

The thing that's interesting about rapamycin is people have even gone back now and done even short, intermittent treatments early in life, and you still get a lifespan benefit. So interesting. We don't really understand all of the things that go into the biology of aging. That's another. I mean, we could spend a whole episode on this, but that's a whole nother mythology, this idea that we're close to solving aging. Like, I'm sorry, guys, we are not close to solving aging, but we don't really understand what the optimal regimen for rapamycin is, Just that it always seems to work, and you can get up to about a 30% increase in lifespan, and you can slow functional declines and diseases of aging across most, if not all, organs and tissues in the body. So it really seems to be slowing biological aging at some root level, as opposed to just impacting cancer or just impacting heart function. The other thing that I find most compelling is with rapamycin in particular, there are now multiple examples where you can look at functional declines that have already happened in the heart or the ovaries or the immune system or the oral cavity. And in just six to 10 weeks with rapamycin, you can actually reverse those functional declines and you can partially reverse molecular features of aging. So, again, I don't like the the phrase Reversing aging because nobody's reversed all aspects of biological aging. That's another lie that people tell. Nobody has reversed aging. But we can reverse features of aging. We can reverse some functional declines associated with aging. And rapamycin seems to be able to do that in mice. And there's interesting evidence in people directionally for some of these things as well. So rapamycin was really the first hit to come out of the ITP. It's been going every year, like I said, since 2005. I think 2009 was the first paper published because it takes a while and other interesting things have come out. So some of the things that I find most intriguing. Acarbose was the next big hit from the itp. That's an anti diabetic drug. So that kind of makes sense. We know metabolic health is really important, but it's probably doing stuff other than just metabolic health to have a big impact on lifespan in mice. Most mice will certainly die with cancer. And I think most people are comfortable saying mice in the lab typically die from cancer, really. So it's gotta be impacting cancer. Estrogens have come out multiple times, so 17 alpha estradiol was the first. And then there's another estriol that also has been shown to increase lifespan in

[A]

mice, men and male and female mice.

[B]

It's larger in males than in females, which is, which is interesting. One of the reasons why I find, and then the other one that I find really compelling are the SGLT2 inhibitors. That's probably my. If somebody's like, what's your favorite drug to do? That's probably the one I would pick. Most people would be like, not rapamycin, but no, the SGLT2, the LT2 inhibitors and the estrogens are particularly interesting to me because there was a study from UK Biobank in people that looked at all prescription medications that had. They had to have more than a thousand prescriptions or something like that, but all widely prescribed prescription medications. And they asked if we do our best to match the health status for the people getting this particular drug, which ones affect mortality. And interesting things didn't affect mortality. Metformin did not reduce mortality in that. In that study. Metformin is a great diabetes drug, but it. I don't think it does anything to aging biology or I shouldn't say that it's not effective at really modulating aging biology in a way that leads to big effects on lifespan and health span. But what did come out were multiple types of estrogens, primarily in women, which you know, that's, that's where it's going to be prescribed. So that's where the male, female thing in the mice isn't completely clear. And SGLT2 inhibitors as a class.

[A]

Right.

[B]

So that doesn't prove these things are slowing aging in people, but it's certainly intriguing and directionally correct. So I think there's a lot of rationale now for really trying to dive into the molecular mechanisms in mice so we can start to tease out how is this working and then see if the same thing is true in people.

[A]

Yeah. So what you're talking about there is we're finding the signals in mice around these four particular compounds that you had

[B]

mentioned, and there are a few others. So there's probably 10, there's 10 or 12 that reach statistical significance, but a lot of them are on the lower side, like very small percentage effects, and a couple of them haven't replicated in subsequent studies by the itp.

[A]

Right, right.

[B]

So I kind of, I mean, my philosophy throughout my entire scientific career is focus on the things that have big effect sizes. And so that's. Those are the, those are the ones that I'm most intrigued by because they seem like they're, they're almost certainly a real effect and they're pretty reasonably sized effects.

[A]

Absolutely. And those four, too, are the ones that, you know, all the longevity enthusiasts, if you search Reddit, those are the four things that people are mostly talking about. Right. Those, and I would say hormone replacement therapy is a favorite of the longevity world, but that already has a long history.

[B]

Right.

[A]

As far as what's coming up, those are the four I see a lot of. And what's really interesting is some of the ones you mentioned that did not have an effect are also not proving out in human studies, like metformin, resveratrol. What was the third one you mentioned? Metformin, resveratrol.

[B]

Oh, nicotinamid, ribosomatic.

[A]

Yeah. Nr. Right. And so now we have a signal that is more than just noise. It's actually a signal that we can apply to humans when we're looking at drugs for extending human lifespan. And so, like, I want to make a big distinction between lifespan and health span on these as well. What you're also saying is there's health span effects to rapamycin in the mice.

[B]

Right.

[A]

Is that correct?

[B]

That's right.

[A]

Is that Also true for STLT2 inhibitors, the estrogen metabolites?

[B]

Yeah, all of these. I mean, again, none of the others have been studied as extensively as rapamycin for broad health Span effects. All of them have shown when people have looked benefits in different health span metrics and also molecular signatures consistent with partial reversion back to a more youthful state. So I think with all of them there's reason to believe that they're not only going to be lifespan modifiers. And actually let me add to that because I think there is, it's an important distinction, right. Healthspan versus lifespan. But I think there's a misperception around the idea that we have been able to dramatically increase lifespan without improving health span. There are a couple of papers in C. Elegans that honestly, I don't think they're very good papers. I don't think we can really measure healthspan in C. Elegans. I worked on C. Elegans for many years, so I know what I'm talking about here. I would not draw any conclusions from those papers outside of those. I'm not aware of any evidence that we can robustly increase lifespan without also increasing healthspan. I think it's a non issue. We don't want to do that. We all agree to that. I think it's a non issue. I do think there are interventions that can improve healthspan metrics without increasing lifespan. I don't know of any that improve healthspan across the entire system without also increasing lifespan. But certainly there are ways to improve health without increasing lifespan.

[A]

Yeah, for sure.

[B]

And that may be where some of these other drugs, metformin in certain populations, nicotinamid riboside in certain populations, can improve healthspan metrics in a subset of people without necessarily significantly increasing population.

[A]

And that was my point. Like we don't know if NR is great for health span and not lifespan. It could be. We just don't know.

[B]

It could be. Again, I'm. It is possible that we will find drugs that at the population level will generally improve healthspan without increasing lifespan. I don't know of anything yet. There are a couple. What I. I guess maybe the way I would think about this, the way I think about it is some of these drugs that, that have had sort of modest effects on lifespan and maybe haven't been reproducible, maybe they are able to improve health span with a larger effect size than they are lifespan. I would put alpha ketoglutarate in that bucket. So AKG is an interesting drug. It's sort of on my, you know, intermediate between tier one and tier two. If I was going to, if I was going to, you know, rank supplements pretty consistently gives healthspan benefits in mice, the lifespan effect is small in one study, not there in the next study. So, you know, I don't, I don't know what that means. NR may be in that category as well. The issue with all of the NAD precursors is that the studies that have shown effects on lifespan are just really bad studies. They're just not, not quality lifespan experiments and they haven't been reproducible. And that seems to be a feature of the NAD biology literature. For whatever reason, just a lot of irreproducible science. And so when I see that in a subfield, it just makes it really hard for me to evaluate. There's a lot of smoke. I just don't know what's fire. And I would say the same thing's true. Although there's a lot less data in the human literature on the NAD precursors. The clinical trials that have been done are mixed. Sometimes there's a efficacy signal, sometimes there's not. It depends on what you're actually claiming you're measuring. But none of them are really high quality clinical trials. And so you just have to kind of be like, maybe. And the idea that NAD generally declines in people is sort of a myth. Maybe it's not a myth, but it's not demonstrated like it is. People speak with a lot more certainty about that than the data actually justify. I actually don't think it's true. NAD declines as we age.

[A]

Well, there's a big paper that just came out just recently about a big study on the total organism, NAD levels actually for humans. What they found did not decline as we age.

[B]

Yeah, no, I mean, that's what I think the answer is. But all of this, you know, you have to recognize one study never tells the whole story. There are technical challenges around measuring nad, so. So I'm not, I'm not saying NAD boosters don't have any value, but I certainly don't, don't feel confident in saying that they do or in really being able to predict who's going to benefit and who's not.

[A]

Yeah, hi, Dr. Shah here. I want to take a minute to talk to you about cellular health. So in my clinics, I've actually seen 30 year old people with cells that look like they're pushing retirement. And I've also seen 60 year olds with cells that look like they're 40 years old. So what's the difference? It's really about how fast their telomeres are breaking down. Your cells, you see, are like phones and they have limited cell phone battery, poor sleep, Stress, processed foods, all of these things can drain that battery way faster than it should. So this is the reason why I partnered with ima. IMA powers that cellular battery. It's not just another multivitamin. It's a comprehensive 92 ingredient formula designed specifically for cellular health and longevity. I'm talking 900 milligrams of vitamin C. That's like 20 oranges worth of DNA protection. The clinical dose of CoQ10 that you need to power your cellular engine. You also get zinc, selenium, vitamin E, alpha lipoic acid. All of these work synergistically for cellular repair and protecting your telomeres. So instead of taking a handful of pills every day and all these supplements, Im8 actually gives you everything that you need in one scientifically form. And this isn't just a theory anymore. IMAID had partnered with Oxford University, the International Space Station, San Francisco Research Institute, and they've done studies and they've gotten this NSF certified to truly power your health. Most people are aging twice as fast as they should. Unfortunately, you don't have to be one of them. Try Im8. I actually have a discount secured for you if you go to DrShaw.com IM8 or go to ImaidHealth.com discount DrShaw and you can get 20% off with my discount code DrShaw. You can also find the link below. Can I ask you an important question about the lifespan extension definition? When you're measuring lifespan extension in these mice, are you saying the average age at which these mice die is at the older end of their lifespan than mice usually die, or are we pushing mice past their theoretical maximum age?

[B]

Yeah, good question. So it can be either. It would have to be a large effect. So we're talking like 30% and up. To really move the entire survival curve past the maximum of the, of the control animals. There are two interventions. I would put rapamycin in the, maybe it does that bucket, maybe on the best of days. The only other intervention that clearly moves you, the animals outside of the normal lifespan range, I would say, is caloric restriction. And so there was a study done, it was published in the early 90s now where they got a 60% increase in lifespan. But these were, in mice that were, the controls were long lived. And this is why I think that percent increase can be really misleading because you'll read garbage papers where the mice lived, you know, half as long as they were supposed to. And then the intervention brought them to their, their, where their lifespan should have been. That's 100% increase in lifespan, it just means nothing.

[A]

Right.

[B]

So this was a 60% increase over a long lived control. And in that case, you know, pretty much all of the animals in the caloric restriction group died after all of the animals in the control group or. Sorry, yeah. They started dying when all of the animals in the control group had already died.

[A]

Already died. Right.

[B]

I think the way, the way though that this is done in practice is when we say an increase in lifespan, what we're usually talking about is median lifespan. So the, where, what, at what day or month or week, depending on the unit you want to use, are 50% of the animals dead?

[A]

Yeah.

[B]

And then is that statistically different between the two groups? There are tools you can use to also look at maximum lifespan. And so often what you'll see reported is the statistical outcome for median and maximum lifespan across the cohort.

[A]

Makes sense.

[B]

One important thing to appreciate if this is going to translate to people, which again, we don't know for sure yet, there is going to be an individual component to this. And that is why I think paired with doing the studies to understand does rapamycin or acarbose or SGLT2 inhibitor slow aging in people? Also understanding which biomarkers can we use to predict which individuals are going to benefit and by how much.

[A]

Right. Is there a biomarker signal that you're aware of right now?

[B]

I mean, the one most people would point to are the epigenetic clocks. Yes, that's very. Again, those are useful research tools. They're useful at the population level right now in research.

[A]

Research.

[B]

They're not useful clinically in my opinion, both because none have been validated for clinical use. And most of the tests that people are using in the clinics are provided by these direct to consumer companies where we have no information about error rates. So I just think it's important for people who use the epigenetic tests right now to recognize there is no difference that's big enough between two measurements that you can statistically be confident It's a real difference.

[A]

Yeah. And I know you did an interesting experiment with.

[B]

I did, yeah.

[A]

Epigenetic clots. Well.

[B]

And all that experiment showed was there's a lot of noise.

[A]

Right.

[B]

But understanding that there's a lot of noise is only useful if you can then put error bounds on that noise. And what I'm saying is we have no error bounds right now. So that's to me the biggest deficit in the companies that are marketing the test. I do think they could one day be useful clinically. The other limitation to the epigenetic tests right now is we don't have a mechanistic connection to why they're correlating with mortality or with disease risk. In other words, we know what we're measuring are methylation marks at specific places in the genome which are going to influence gene expression at those locations. What we don't have is a connection between the specific gene that this epigenetic mark is regulating and longevity or mortality or disease risk. So we don't have that mechanistic connection. So it's just a, it's a pattern. We don't really know what it means. We don't know which populations or individuals it's going to work for. I still like traditional blood based biomarkers and functional measures as the go to. When you're thinking about biomarkers that we can be pretty confident are telling us something about health. I would love to have a really gold standard biology of aging biomarker. We just don't have it. Right.

[A]

We just don't have it right now. So that brings me to your canine experiment that we're doing. And if you can talk a little bit about that.

[B]

Sure.

[A]

You're testing rapamycin on dogs.

[B]

Right.

[A]

And I'd love to know what you're measuring, kind of how you set this experiment up and tell us all about it. The Dog Aging project.

[B]

Yeah. So we have a clinical trial of rapamycin in companion dogs. So first thing to say, these are all companion dogs living with their owners. We don't do anything in dogs in the laboratory. The rapamycin clinical trial is really only a small part, at least in terms of number of dogs, of the overall dog aging project. So the dog Aging project, you know, was really started with two goals. One is to understand aging biology in dogs. And what I mean by that is what are the most important genetic and environmental factors that influence health and longevity in companion dogs living with their owners? The second goal was to do something about it. And that's where the clinical trial comes in. So there are 50, probably almost 55,000 dogs and owners now all around the US participating in the Dog Aging project. The vast majority of those dogs are observational. So we're collecting data from the owners from a subset of dogs. We get whole genome sequencing, metabolome, microbiome, epigenome, veterinary records, things like that. That's all with the goal of correlating health outcomes to factors that might influence health. So genetic factors, diet, exercise, other animals, being around.

[A]

So you're kind of running this like the UK Biobank for dogs.

[B]

Yep. Exactly.

[A]

Yeah.

[B]

And one of the reasons why I think this makes so much sense, aside from the fact that many people consider their dogs to be part of their family. Right. So if we're successful at improving health and longevity of people's dogs, there's intrinsic value to that. Dogs also age very much like people do from a biological perspective, but they do it seven to 10 times faster. Meaning that what would take 30 years from a human observational study, we can do in three or four years in dogs. And so the rate at which you can accumulate data and generate hypotheses from this sort of an observational study is much more rapid.

[A]

Right.

[B]

So that's most of the dog aging project. Having said that, you know, what really got me excited and, you know, led me to really pushed to create the dog Aging Project, I should say. Dog Aging Project is a joint project that three of us. Myself, Daniel Promisloe, who's now at Tufts, and Kate Creevey, who's at Texas A and M, started 2014 or so. Daniel and Katie had been thinking about observational studies of aging in dogs. Well, before this, what really motivated me to push it forward and create the Dog Aging Project was the idea of, frankly, making my dog live longer. And it was. I had a German shepherd. His name was Dobby. I lost him. It's been a year and a half now. Yeah. Thank you. It was brutally difficult, but he was the inspiration for the dog aging project. And it was through a series of conversations with Daniel that I had this light bulb moment where I was like, in my lab, we were studying rapamycin. We were studying caloric restriction. It was like, we're studying these things in mice. They're the field. We have probably eight or nine or ten. Some of them are going to work in dogs. And then I was like, oh, my God, we could slow aging in dogs. And so from that moment, I felt like I had to really do this. And so, first question was, what do we test? Right. And for all the reasons we sort of already talked about, it was either rapamycin or caloric restriction. Those were the two that had the best data. Getting owners to calorically restrict their dogs would be a real heavy lift. So rapamycin was sort of the obvious choice.

[A]

Wow.

[B]

So then the question was, you know, could I get money to do it and could we do it safely? Again, people consider their dogs to be like their children. So I approach this very much like a pediatric clinical trial. You want to absolutely make sure you're not going to hurt anybody's dog. So we were fortunate that at the time, there were some studies of hemangiosarcoma and osteosarcoma in dogs going on with rapamycin. So we were able to talk to those investigators, get some dosing information, understand where we could be confident there wouldn't be side effects. And then with a lot of sweat equity, I scraped together enough money to do a short 10 week clinical trial. And so that was our first foray. It was my first foray into doing clinical trials at all. And, oh my God, I have learned so much over the last 10 years now about all the things that make clinical trials difficult, but it's been a great experience. So in that first clinical trial, we designed it as a 10 week study. Again, safety was the primary thing we were interested in. Right. But we thought because people in mice at that time had shown that by echocardiogram, which is ultrasound for the heart, you could see improvements in age related changes in heart function. So we thought, we're going to do this trial, let's go ahead and give the dogs echocardiograms before and after. So we did the study. It was relatively small. I think we had 24 dogs. All of our studies are randomized, placebo controlled, double blind or triple blind, if you want to include the dogs. Clinical trial. So the vets don't know, the owners don't know. Dogs presumably don't know if they're getting rapamycin or the placebo. So a couple things came out of that study. One was no safety signals, which was great. Owner reported. So every week the owners got surveys. They didn't know if their dog was getting rapamycin or placebo. So owner reported improvements in activity and quality of life. And then by echocardiogram, two of the three endpoints, which were all left ventricular function endpoints. So how well is that left ventricle contracting? That goes down with age. We saw statistically significant improvements. In the third, it was directionally going towards improvement as well from rapamycin.

[A]

In just 10 weeks.

[B]

In just 10 weeks. But that fits really well with the mouse study.

[A]

Yeah.

[B]

And again, in mice, six to 10 weeks is enough to reverse functional changes in the heart, the immune system, the ovary and the oral cavity. So the interesting thing is there's a hint in people. So there have been studies with a derivative of rapamycin called everolimus that six weeks of treatment with everolimus is enough to boost immune function as measured by a vaccine response in healthy older people. That fits pretty well. I mean, this would Be a deep dive into MTOR biology. But that fits pretty well with the idea that one of the things that MTOR does when you turn it down, which is what rapamycin does, is it blunts chronic sterile inflammation pretty rapidly. And I think when you do that, then you see these functional improvements show up.

[A]

So interesting.

[B]

So anyways, that was the first study. Then we started again, went back to raising money, got fortunate to get a philanthropic grant from a foundation called the Donner foundation that funded the second clinical trial, which was a six month clinical trial that was done at Texas A and M University. That trial also showed owner reported improvements in quality of life and activity. And again, no safety signal. One dog got high triglycerides, which is a known side effect of rapamycin in organ transplant patients. There's probably a genetic component, but the nice thing is all of the side effects in the organ transplant patients and in this dog that got high triglycerides went away as soon as the dog came off rapid mice. So as long as you monitor, not a big deal. Dogs don't get vascular disease really. So it's not a huge issue there either. That's the only dog we've ever seen that in. And then we finally, after six years, got the first NIH grant to fund the project. And that allowed us to start on what is the ongoing clinical trial now. So we have a clinical trial called Triad test of rapamycin in aging dogs. 580 dogs. It's about half enrolled with lifespan as the primary endpoint. So that 580 we believe gives us the statistical power to detect a 9% change in lifespan. And so I mentioned early on the very first study with rapamycin in mice, 9% in males. So that's the lowest I'm aware of that's ever been reported. And so that's what we powered our clinical trial to hopefully be able to detect. So lifespan's the primary endpoint, but we're looking of course at a variety of healthspan metrics as well. So half the dogs get echocardiograms at every visit, half the dogs get neurological exams at every visit. All of the dogs get full veterinary exams, genomes sequenced metabolome, microbiome, epigenome and clinical chemistry.

[A]

580 dogs. Yep, that's fantastic data.

[B]

And it's a three year study period. So every dog gets treated for one year again, half placebo, half rapamycin, one year treatment, two year follow up. We've got about 20 clinical sites. Those block randomized at every site I mean, we really tried to do this to the very highest standards. We're not going for FDA approval or FDA label expansion, but we really tried to build the clinical trial to the very highest standards so that we can have confidence in whatever we see. So, you know, I wish I could tell you that, you know, we're going to know the answer next year, but given the way that the trial, you know, is going, it's probably a year from full enrollment and then the dogs have to treat the. Have to finish the study period.

[A]

Yeah.

[B]

Once all of the dogs have completed the one year treatment, we will do an interim analysis. We may be able to say something about some of the endpoints, but I don't think we're going to know for lifespan until all of the dogs have gone through the full three years.

[A]

Sure, sure. And how does. Let's assume that the signal turns out that it's the same signal you've seen before with echoes and with lifespan improvement. And this is incredible, rigorous, good research on this. And now we've gone from mice to dogs.

[B]

Right.

[A]

And so we already know rapamycin's FDA approved. We already know there's a high safety signal. How do humans or people then look at the results of this study and then make a determination about like whether they should be trying rapamycin or not?

[B]

Yeah, well, this is, it's actually interesting because there's a lot of concern around safety with rapamycin in humans, primarily because of the way it was clinically developed and approved as an organ transplant drug at high doses. In people taking strong immunosuppressants, there are side effects there. I'm not going to try to say there aren't. They're not life threatening, but they're not. Fantastic. So now there have been probably tens of thousands of people by this point who've used rapamycin off label and we actually have a pretty good feel for what the safety signal looks like. It's pretty non existent. 15% of people will get mouth sores. Outside of that, I haven't seen anything that's statistically significant. Maybe a little signal for, you know, glucose perturbations or bacterial risk, but it never reaches statistical significance. So I think we know how to use it safely. I think rapamycin is one of the few cases for off label use of an FDA approved drug where we have reasonable evidence across multiple age related domains that we can look at and make an informed risk reward calculation. I'm not suggesting everybody should be taking rapamycin. I'm not convinced it Slows biological aging in people. I would say if. If you forced me to, like, make a guess, I'd say, yeah, rapamycin, SGLT2 inhibitors, probably slow biological aging in people. GLP1s maybe. But I'm not confident enough to say, like, yeah, we have a lot of good data there. I do think there are use cases where rapamycin makes sense in people. But if you ask me as well, like between SGLT2 inhibitors and rapamycin, what would I feel most confident suggesting that people could use? Safely off label, broadly speaking, I'd say the SGLT2 inhibitors. So that's kind of where I'm at. And again, we could spend a whole episode talking about the different human data on rapamycin. There are a lot of signals for different conditions. I would put any chronic inflammatory disease, likely chronic fatigue syndrome following viral infection, very likely. Really good data there. If you're an APOE4 homozygote, there's not a lot, but I would say pretty compelling data for rapamycin in that context, both for cerebral blood flow and volume changes in the brain, both of which we can measure. The nice thing is we've got biomarkers there we could measure. So those are places where I think fertility. There's a use case.

[A]

Yeah.

[B]

There's one study out of China looking at in vitro fertilization in women and showed an effect of rapamycin there. There's another clinical trial out of Colombia that has completed. They haven't released the results yet. That's Yushin Su and Zeb Williams looking at premature ovarian failure in women. So early signal. That's where I feel like there's maybe not quite. I mean, again, it depends on your personal situation. Right. Maybe not quite as much evidence, but again, if you've sort of evaluated the entire equation and you feel like it's right for you in that context. Yeah. I will say, and again, a lot of this is just anecdote. You talk to a lot of people. Rapamycin definitely does stuff to the ovaries, I think we just don't really know exactly what it's doing at this point. So there is a signal there for sure.

[A]

Right, right. And so it's an exciting time. I think we have a lot going on. We talked about peptides, we Talked about rapamycin, STL2 inhibitors, which we didn't even get to, but people can do some research there. I'm on Evocata myself. Are those gonna come off patent soon? They're so expensive.

[B]

Which ones?

[A]

Evocana. The STLT inhibitors.

[B]

I don't know which ones are on patent and which ones aren't actually, to

[A]

be honest with you, I'm sure there's, they're all very expensive right now.

[B]

Yeah, I'm on giardiance and. But you know, with insurance, it's not bad. It's like. Yeah, not $36 a month I think, is what I'm saying.

[A]

Ah, I see. So maybe I need to switch over to that one then.

[B]

I mean, this is a whole nother thing. Like the expense of these pharmaceuticals. You know, it's such a game. Like you can, you can submit your pharmaceutical drug prescription, you know, and it'll, it'll be $500 and then you go get a coupon and it's $40. But you need to know the coupons

[A]

there to get it.

[B]

It's like, can we just fix this system? Yeah, it's ridiculous.

[A]

It's kind of ridiculous. But I mean, I really feel like this is an exciting time because there's, there's a lot of new research coming out, there's old research, there's research that you're putting out there that really does kind of give you signals. Right. And so I'm hoping that we can just accelerate the research to your point and find a way to really accelerate this because. And maybe that solution will come with AI, will come with data crunching. It'll help, I think.

[B]

AI will help. Yeah. I think what I would say is the thing I'm most excited about is this. There does seem to be a shift in mentality. And again, you know, for as much as I get frustrated sometimes with the big name people who are getting a lot of attention because they aren't very scientific, I think they have helped the discussion and there is a shift in mentality both among medical providers and among the general population towards recognizing that proactive health is what we should be doing. Keeping people healthy is way better than keeping people sick. And so that's very encouraging. But along with that comes this rush for shiny object latest experimental therapy. So what I think will happen is we'll get more and more mainstream medical community taking rigorous approaches to proactive healthcare. And so we're gradually going to get this type of quality healthcare available to more people. And really that's, I think what we need to do. There's always gonna be the people who wanna try the experimental stuff and that's fine. If you wanna do that, great, go do it. But I think for the average person creating a system where they can get access to evidence based proactive healthcare will give everybody, I think the opportunity for between 10 and 20 more years of healthy life. So this is a big deal.

[A]

It's a big deal.

[B]

And so there is a lot of reason to be excited about that and also to continue to try to push forward this science and the evidence based approaches.

[A]

Imagine. Right. And for the first time ever, I'm seeing many physicians getting involved in the conversation. Whereas before there was no, it was just like a hard stop on conversations around these type of health span promoting therapeutics. And now people are talking about it

[B]

and even the people who are particularly critical of the field are at least having the conversation. Exactly. So that's good.

[A]

Exactly. And I credit you for a lot of this. So thank you so much for putting this work out there and doing the hard work and it was such a pleasure having you on the podcast.

[B]

Thank you, thank you. It's been a pleasure.

[A]

Where can people learn more from you?

[B]

Yeah, so I'm on Instagram and X and LinkedIn, Caberline and I've got my own podcast on YouTube also. Kaberline, thank you so much. Thanks.

[A]

Thank you so much for listening to the podcast today. Please remember to subscribe if you like this episode and give us a good review and share a link with your friends. It really helps to support all of our efforts. I also want to remind you that the information shared on this podcast is for educational purposes only and is not intended to replace professional medical advice, diagnosis or treatment. Please consult with your healthcare provider or physician before making any decisions or taking any action based on what you here today, especially if you have any underlying health conditions or on any medications. Your doctor knows your personal health situation the best and it's always important to seek their guidance.