Longevity / Longevity Medicine Needs Evidence More Than Momentum
Longevity medicine moves quickly. New drugs, peptides, biomarkers, and cautionary stories arrive almost every month. Speed can be useful, but only when it is paired with proportion.
Longevity / Longevity Medicine Needs Evidence More Than Momentum - Full Transcript
All right. Hey, Marcus. Thanks for uh joining me again on Longevity Science. I know we were hoping that Brian Kennedy would be here with us today, but he unfortunately had to cancel at the last minute. So, it's just you and me. So, you're on the hot seat today. You've got to be the one to make this an interesting conversation. Uh so, we've got a few topics that we're going to dive into. Uh are you ready to go? I'm ready, Max. I'm ready. Clearly Brian's got more fun happening, so it's just the two of us today. Yeah. Well, that that's that's pretty pretty normal. Uh, so let's start with peptides. I know this is a topic that we seem to keep coming back to and everybody wants to talk about. I think the big news and peptides these days is the FDA and their uh process for determining which peptides are allowed to be compounded. uh they just had a committee meeting the last last week I think to vote on a set of uh seven or eight peptides that had been previously moved off of the list that was allowed to be compounded in the United States on whether those peptides should go back on to the list. Uh it's my understanding that the committee recommended that six of the seven uh be moved back onto the list for compounding. Um I kind of just like to get your thoughts maybe in general about peptides this process. Do you think this was a good development uh or do you think it was a bad development or do you think it just honestly doesn't matter at this point? Look, uh you're obviously much closer to this being in the US from the outside in. Um uh you know, my key question is is that decision to go back on the list based on any any clinical evidence or is there ulterior uh sort of political
there ulterior uh sort of political suggestions uh at play. Uh that for me is obviously a big thing. Look, I I think they're pros and cons and we can talk about the benefits, but before we do that, you know, was this decision based on data or what was the core of the chain? Yeah, I mean again, I think different people are going to have different opinions on that. So, from what I've been able to determine, the FDA scientists recommended against moving these things back onto the compounding list. And that was supposed to be based on, you know, has any additional data been generated since the decision was made to move them off of these bulk drugs lists um to warrant moving them back on. And and the FDA scientists felt that there had not been any additional data on safety or efficacy that would warrant this decision. So I think it's hard and again my read you know of the literature which is pretty much non-existent on most of these peptides at least in humans would align with that we really don't have much more in the way of validated data on safety and efficacy to to change the equation. Um so I think on that side it's hard to argue that this was a datadriven process. Having said that, you know, I think there the other question you raised was around, you know, are there other motives, right? In other words, you know, are the people who are on this committee connected financially or otherwise to the peptide industry in ways that might cause people to think that this was, you know, a profit driven or politically driven process. I think if you look at the list of the committee members, it's easy to think that might be the case. And that was my initial impression because several of the committee members have ties to the peptide industry. As I dove into that a little bit more, I was surprised to find that when you look at the way the the members of the committee voted, it seemed to be the case that it's actually the more traditional academic and medically
traditional academic and medically oriented people that tended to vote in favor and the people who I would have thought of who would have these conflicts voted against in general. So, I'm less convinced that's actually a major um component of the the process. I do think there are political forces at play clearly, but but I I'm less worried about the financial piece after looking into the way that the individual committee members voted. But I think the appearance is there, which is really what you said. You know, from the outside in, especially for people who don't don't really look into the process, it's easy to think that there may have been financial or political motives at at play, that this wasn't a truly evidence-based process. And again, given the lack of data, it's hard to argue that it really was a data-driven process. At least that's my opinion. Yeah. So the way I'm sort of thinking about it and even counseling just today I had a a call from um uh you know prospective patient or client asking about this recent change and whether it's going to change the way we practice in the clinic and the way I responded was look um uh the the decision to change the nomenclature of a substance without any sort of clinical uh data underpinning it is not going fundamentally influence the decision about whether we use it or not. Um my hope is that when this happens uh maybe the most speurious actors because of a gray market and you know you and I and Brian on our last chat had a long long discussion about that. So I'm I'm hoping that if you validate this formally then those furious actors will be lesser and there'll be cleaner product potentially available by reputed brands. So the safety element potentially becomes less of a concern but that doesn't mean the efficacy efficacy uh conversation goes away. And
efficacy uh conversation goes away. And just to reiterate the FDA changing its stance doesn't mean that suddenly this is a proven class of molecules. It's just saying that, you know, a group of individuals feel that it no longer needs to be on a blacklist or whatever. Yeah. I think that's a really important point and that's that's one of my concerns is that I think a lot of people in the general public may be confused into thinking this means that these things are now FDA approved and that there's legitimate safety and efficacy data and that's that's absolutely not the case. It just means that that compounding pharmacies are now technically allowed to manufacture these peptides into formulations that doctors can can prescribe it. It there is absolutely no additional data on safety or efficacy uh that is driving this decision apparently. Um I think the other thing that's that's worth um just mentioning because I think a lot of people assume that now suddenly these peptides are going to be available through compoundingarmacies. This is really just the first step and it's probably unless somebody accelerates the timeline another 8 to 12 months from this committee recommendation before the formal approval gets into place where compoundingies can legally compound these peptides. And it's not even 100% guaranteed that that formal approval will happen just because of the the committee recommendation. Um, yeah, one of the things I want to just briefly double click on that you said is, you know, you said for you this isn't going to change the way you evaluate peptides. You use them in your your practice. I think that's the right uh way to think about it. But I also think that many of the doctors who are already using peptides won't think about it that way. And in fact, this will be a catalyst for more doctors prescribing experimental peptides to their patients. How do you feel about that? And and I mean, you
feel about that? And and I mean, you know, do you think again that this is a problem or it's just sort of something that's going to it's going to happen regardless? So it doesn't really matter what what FDA does in this context. So I mean I think at a I mean sentimentally I'm a little bit split. I I appreciate the need for innovation and clearly you know there's always going to be people who want to push the boundaries push the frontiers and you know whether it's selfexperimentation or you know utilizing it in people who are willingly consensually uh taking the risk and and willing to see if there's any benefit. Um so in that group of individuals I think this could potentially be a benefit because it'll be hopefully uh in 12 months from now it'll be cleaner substance available for them and we have to be less concerned around heavy metals and additives and and just sort of uh uh strange additions to it. But um I mean I'm still still unfortunately unconvinced. Uh I'm I'm cautiously optimistic. Uh as a phrase that I I borrow sort of from your your narrative. Um I am cautiously optimistic, but I'm unconvinced. I've had three experiments on self. Uh and I've openly spoken about this. There was an oral version. There were two injectable forms. None of them yielded any uh objective, nevertheless any subjective gains for myself. uh I've got five to 10 individuals I know uh who are under my care for other reasons who are taking peptides uh and even there you know there's not been a single significant biomarker shift uh that is convincing enough to say wow um you know let's take note of this. So yeah I I'm watching and waiting. I'm hoping there'll be a body of evidence, but um I don't know how quickly that will come, honestly.
how quickly that will come, honestly. And and just to be clear, so in your case, I think you were you you were specifically referring to BPC 157 for yourself, right? Uh BPC 157 and then in combination with TB500 as well. Yeah. Okay. Great. Yeah. I just think again, I mean, you know this, I know this, uh peptides include a lot of different things and there are FDA approved peptides. We're talking here specifically about a set of seven specific unapproved peptides that fall in the experimental category. Um, and just just to be uh explicit, BPC 157, TB500, those two you mentioned were on this list. Both were recommended to be put back on the the bulk drug list for compounding. The others were K KPV which I don't know much about, Mati which is a mitochondrial derived peptide, samax, epitalon and emidelide which I also don't know a whole lot about. That was the only one that was rejected of the [clears throat] seven by the committee. So these are experimental and that's the problem that that we don't in most cases have very much in the way of safety or efficacy data at least that meets the standards we would expect. It's anecdotal and so from your anecdotal experience, you're not seeing much. There are other, you know, peptide experts who claim that, you know, they're seeing amazing results in their their patients. And so, this is why we need the clinical trials so we can separate signal from noise. And um my sort of view on these peptides in particular aligns with yours given what I've seen talking to lots of people. I've tried BPC 157 myself. it. I think these things have some biological activity, but they don't move the needle the way that certainly diet, exercise, sleep, you know, friendships do. They don't move the needle the way hormones do. They don't move the needle the way GLPs
They don't move the needle the way GLPs do. So, they're incremental at best is what I would say in terms of efficacy. And the safety risk is unknown. The the last thing I'll just say on this to I know you said it, but again, just to be explicit, I think the hope is that by putting these things back on the compounding list, it will deincentivize the black market, which is where we're running into impurities like heavy metals or endotoxins or other things that can be harmful. That remains to be seen. Again, I'm not convinced that will be the case because I still think the black market peptides will be cheaper than the compounded peptides. And so there will be lots of people who gravitate towards the the cheapest option that's out there. So time time will tell I guess. Um okay. So the second topic which is related you know to this impurities question. I think you may have heard about this uh this young woman in New York who was getting an NAD infusion and apparently we don't know exactly what happened but died very very soon after getting the the NAD infusion. So again, for people who haven't heard this story, this happened 10 days ago. So July 19th, 27year-old woman named Elizabeth Baron in New York City received an NAD infusion at Barishit Lifestyle Center. That's the name of the place. I didn't make that up. Uh in the Bronx, uh fell unconscious almost immediately. Died a few hours later at the hospital. And I think there's a lot here that we should talk about. One of the issues is that the person who gave her the drip, Luis Rojos Cabrera, was not a licensed physician in the United States. Apparently had a medical license from the Dominican Republic. Um, so that's a problem. Uh, and the cause of death hasn't yet been determined or if it has, I haven't seen the reports. Initial people are saying cardiac arrest. So, um, what were your initial thoughts when
um, what were your initial thoughts when you heard this story? And I mean, look, it's very sad and obviously it reminded me of that case a few months ago at that wellness festival where something very similar happened uh in in the US. Um, and in that case that was peptides. Yeah. Right. But just this idea that you know in an informal environment in an unregulated setting an individual goes to a position who is you know supposedly in a position of care and has a duty of care uh and administering something and then it leads to a fatalistic event in someone young. It's it's very very sad. Um and it's a very very strong reminder in fact for everyone that uh you know these things uh you know it's it's falling under a wellness trend unfortunately we're seeing so many of these wellness clinics spring up everywhere which are offering infusions and NAD is one of them and therefore people may succumb to the idea or the belief that just because they hear it on social media and now it's being made available through an IV drip uh that it's safe, but it's not we we don't have all the evidence. We don't know all the information about these substances. Um and uh and and we we must must be cautious about putting things in such high doses. Again, you know, I self-experiment like all of us. I experimented with an NAD infusion a few months ago and by a clinical oncologist uh who gave it to me under supervised conditions. Did my bloods before. So we did it in as safe an environment as possible and I felt this subjective crushing sort of central um uh not pain but it's a strange feeling of chest tightness with a significant shortness of breath
significant shortness of breath almost akin to being at sudden high altitude exposure. was that sort of uh feeling. Um and uh and it was incredibly uncomfortable and I was just thinking, you know, yeah, what a fine line this is between complete discomfort uh and some significant event. So uh this just is another reminder that we have to be careful and that our industry of of preventative health of longevity can significantly be tarnished by you know rogue actors and sorts of ill effects. Yeah. probably already has been tarnished, I would say. Well, we we can come back to that in in a few minutes, but um your your uh description of what you experienced is really interesting. I was just talking to a woman two days ago uh who had had also only once done an NAD infusion. She described exactly the same sensation that you just described, this sort of crushing weight on her chest. She thought she was having a heart attack. Again, I mean, I think, you know, it's unclear whether the NAD caused the death in this case or if it was an impurity. We kind of have to wait and see. Again, the initial reports are cardiac arrest, but I would just say, you know, clearly the NAD drips are having some sort of profound biological physiological effect. If people, even if it's a subset of people, if a significant subset of people are feeling this response, that means it's actually doing something significant to your physiology. And I would suggest that an unnecessary intervention with unclear benefit, if any, that causes you to feel like you're having a heart attack should give responsible medical professionals pause about giving that to healthy people. Like this just makes absolutely no sense to me. [laughter] Um, so uh, so in your opinion, I mean,
so uh, so in your opinion, I mean, again, you're you like to experiment. You try things. Uh, is there any reason why healthy young people should get NAD drips at this point? Like, is there any rationale for that? That makes sense. I I after this event, I cannot think of a convincing reason for an NAD infusion. Uh that being said, perhaps there's another conversation we can have about their precursors and whether an oral supplement uh in a different dosage may have a differential effect for different types of populations. Let's just park that to one side. But but certainly until we have the the information on this particular case and and until we get more data again around this uh I think high dosage of infusions like this you know it's just um it's it's a scary environment for sure. Yeah. Okay. Um yeah. So I mean let's talk about the NAD precursors and the rationale for for NAD in general. I mean, I I know you know this and and you know, most people will have heard that, you know, NAD levels decline with age and therefore if we can restore NAD levels, there may be some benefits that go along with that and there's some mouse data to support the idea that boosting NAD through the oral NAD precursors can have some health span benefits. The lifespan data not really reproducible, not very convincing. So, we'll just say maybe for lifespan, but for certain health span metrics, it seems reasonable in mice that these oral precursors may have some health span benefits at least for certain conditions or certain individuals with with genetic predisposition. So, um so talk a little bit about that because you brought up the idea that NAD oral NAD precursors might be a better option. What are your what's your current thinking on that? Well, I mean, you know, looking at the
Well, I mean, you know, looking at the mechanistic uh, you know, pathways um, and some of the mice data, there's been this story for so long. I I know the ITP also ran some sort of mice related studies, right, in in 2020. Yeah. Right. And and did that um I I can't remember the exact data but did that show that the levels went up but there was no real change in lifespan right yeah I don't think in the life so so the way the ITP works is usually they do some some preliminary uh experiments looking at bioavailability and pharmacocinetics of the intervention but then in the mice where lifespan is measured they don't you typically do those kinds of experiments so I don't think in the mice where the lifespan was studied that they measured NAD levels. So there's a couple things to say about that. So just for historical background, there was a paper from Johan Hows's lab uh in aged mice where they first reported that nicotene ribocide could extend lifespan starting the treatment at like 20 months of age, mouse equivalent of about a 60-year - old person. The effect was modest, but it looked real. Um and then the ITP attempted to reproduce that in their sort of much more rigorous triple triplicate replication sort of model. The um they did not see any effect on lifespan uh using the same dose that the Outworks lab had had used in that context. Um but I don't think they measured NAD levels in those mice and it was a different genetic background. So I think what we can say is you know it's the experiment's been done twice. You can make a certainly a reasonable argument that the ITP experiment was much higher quality. Many more animals performed at three different sites. No bias for them to get a certain result. But it doesn't disprove the possibility
But it doesn't disprove the possibility that that nicotenomid ribocide or other NAD precursors might increase lifespan in mice. It's just something that I think anybody who's being you know honest or unbiased would say it's not so convincing at this point that nicoten ribocide can increase. And then there was some uh sorry there was some more more recent work uh where they had taken was it muscle biopsies in older healthy individuals who are fit and active and uh there the delta was not I mean it was comparable to a young healthy individual right in terms of their NAD levels. Yeah. So there's yeah there's a lot here uh to to unpack uh probably more than we can really get into but I think what you're getting at is there's two questions I think one is um does do NAD precursors nicotenomid ribocide nicoten monucleotide change NAD levels and maybe three questions do they actually change NAD levels in mice andor people? Does NAD decline with age in mice andor people? Um and then are there any benefits if you can prevent that decline in mice or people? Right? So six if we do a three three by two you know two organisms three questions six way uh six different questions we're we're trying to answer. So here's the way here's where I come down at this point, right? Um, and the other thing that's worth saying is there's also nicotenomide monucleotide which is kind of the other common oral NAD precursor that's being you know talked about sold uh broadly uh uh today. Um nicotenomid monucleotide uh also has been reported to increase lifespan in mice that came out of David Sinclair's lab. Um, but those mice were super short-lived. I mean, this is a classic bad mouse lifespan experiment. And the supposed, you know, lifespan extension by by NMN didn't even bring the mice back to where a
the mice back to where a control animals untreated should live in a well-conducted experiment. So again, I think if you're being unbiased, you have to say maybe like it's completely unconvincing that this is a a real effect. So that's the part of the problem with the NAD precursor literature in my view is you have a whole bunch of may you have some signal but then you also have you know irreproducible results and so it's really hard for me to have much confidence in that body of work overall. Okay so that's the kind of the lens that I look at this through. So in mice um do NAD precursors increase NAD? I think the answer is yes when dosed appropriately. Like it is possible to boost NAD with oral NAD precursors in mice. Um does NAD decline with age in mice? The answer is unclear. There's a signal in certain tissues but but not globally. And so that's been way overstated but probably in some tissues NAD declines with age in mice. Uh maybe not in all mice but in at least a subset of animals. And then do NAD precursors increase lifespan and or health span in mice? Probably. Well, maybe I think is the answer if we're being honest. Not consistently and not to a big effect. So So it would be incremental at best compared to other things that do affect lifespan in mice. It's sort of where I land on the mouse side. On the human side, it's very similar except with even less certainty, right? And I think the big question in my mind is does NAD actually decline with age in people at the population level in most tissues, in some tissues, in any tissues. That's completely unclear. And this is my biggest frustration with the the NAD world proponents is is they'll get out there and make statements like NAD declines with age. And that's
NAD declines with age. And that's completely unclear in humans. Like if you actually talk to real experts in metabolism, they look at the longevity [clears throat] folks and they're like, "Those guys are jokers, right?" Like they're I mean, this is a problem in longevity is I think scientists in other fields look at the longevity people talking about NAD and they're like, "This is a field full of people who are not good scientists." So this is, I think, something that needs to get worked out, but it's it's a it's it's very problematic when when, you know, experts in the biology of aging just make broad statements like NAD levels decline with age. That's unclear. Probably not true, at least at a global level. And now we have papers coming out, at least in blood, now we know NAD levels actually don't seem to decline with age in humans. I suspect we're going to find that's true in in other tissues as we start to get more data as well. So yeah, the quality of the science is just not high in the NAD field, unfortunately. Overall, there are some good people, some good scientists, but the quality of the science just isn't high. So I have a hard time knowing where to land on this. There's lots of smoke. I don't know if there's any fire, and I've been saying that for a decade, and the fact that I still don't know if there's any fire makes me think there might not be any fire. But we'll have to wait and see. So, I don't know about the NAD precursors. Sorry, that was a long diet tribe, but um you know, it's it's frustrating that we aren't further along with the NAD uh data at this point. I think I feel like we should be. And the human clinical trials you referred to are fine, but they're small. The effect sizes are are usually pretty minimal. I think what we can say is the oral precursors are probably pretty safe in people. I don't know what what's been your experience. Do you use NAD precursors personally or when your your patient up to about 6 months ago? I can't remember when that nature paper came out
remember when that nature paper came out uh with the human data, but I I think it was about four or five months ago, but up until that point, I reservedly used the precursors in an oral format for two types of patient. And and I just want to caveat this for everyone watching, right? Um just because I may be doing something doesn't mean that it's the correct approach. And secondly, you know, as a clinician, our job is sometimes the hardest because we have to sort of translate what the scientists are doing and then figure out well in which patients can I actually maybe try this on or use this to their benefit because we want to do good work uh as well. So uh there were two subsets of populations where I would occasionally use the um the precursors. one were in frail uh uh individuals above the age of 65 where I was taking a estimate that uh you know if NAD levels were to decline with age this was the group of people where there was likely be the largest decline uh given there was sort of global frailty and uh uh about 500 um uh 500 mg once or twice a day uh as a dose Um did you have a preference for NR over NMN or or which way were you leaning there? Uh in India um uh we only really have one reputed brand which produces this locally uh and uh I think it's an NR from memory uh that they're making uh and and using. Um so that was one population and I will say that anecdotally uh these individuals uh saw benefits. Now again it's hard to disassociate from all the other stuff because I'm also looking at supplementation. I'm also looking at sleep. I'm using creatin. I mean there's all kinds of other stuff going in. So it's hard to dissociate one effect but anecdotally uh there was some sort of subjective
uh there was some sort of subjective benefit in the in that group. And the second group uh were you know really high performance individuals, athletes, weekend warriors who are pushing the body. And there my thought process was that is could this potentially be a rate limiting step where substrate uh becomes a blocker for you know bioenergetic production at maximum output and therefore could the levels be uh sort of super physiologically augmented so that it's available at the cell in the mitochondria when required and in that group of individuals again there's very there's no biioarker to measure uh and that group is very prone to the power of placebo as well and her mentality. Uh so again they would claim and they would see uh potential benefits. So these are the sort of the two populations where I was using this as I said up until 6 months ago. Since then I've largely stopped um and awaiting further evidence really. Yeah. I I that I think it's interesting that you bring up the athletic performance piece because that to me the data that I've seen and again there's not a lot of it out there but there are a few studies on like you know running clubs and uh uh ultraong uh sort of extreme uh athletes um with NAD precursors showing some benefits. other small studies and again the effect size it's not like you know like anabolic steroid level performance enhancement but consistent it seemingly effects so so it makes sense to me that in that context where you're really you know stressing the system uh metabolically energetically you're right if that if NAD becomes rate limiting in some context that going to superphysiological levels may allow you to get a little bit more you know juice out of the engine maybe similar to creatine, right? Creatine probably becomes important only
Creatine probably becomes important only in certain situations where you know you have depleted your ATP reserves and you need that sort of battery backup, right? Um so again that that kind of makes sense to me and I would I'm more inclined to believe that at this point given what I've seen than I am the the longevity or the the aging benefits. But again, I it's certainly possible, plausible, believable that if you tweaked NAD just right, given what we know, how many different processes that it's involved in, that it could have some benefits in the context of aging. I just feel like the this the the noise around NAD is way way like orders of magnitude above the actual signal at this point. Yeah. Agreed. Okay, let's shift to PCSK9. So, um, so first question is, so the the context here, and I put an episode out on this fairly recently, is that, um, FDA just approved the first oral PCSK9 inhibitor. It's called Enlicitide. Um, but let's start with P PCSK9 inhibitors in general. Is this a big part of sort of what you think about when you're looking at cardiovascular disease and and treating your patients? What's the landscape in India right now on you know PCSK9 inhibitors versus statins versus other types of uh cholesterol lowering approaches. Yeah. No, this is certainly exciting news and and maybe a brief explainer for for people watching who uh aren't familiar with this new class of drug. Um you know what what we're talking about here is a lipid lowering drug. People are probably very very familiar with the statins. Uh people maybe are now increasingly familiar with some of the alternatives like aetami as sort of a dual therapy or combination therapy. Um, and for those not familiar with this, sort of the mechanism as I understand it is that hpatocy, that
understand it is that hpatocy, that liver cell which has an LDL receptor waiting for the LDL particle which is sort of quote unquote the bad cholesterol to be captured which is then engulfed and then broken down for the LDL receptor to then make its way back onto the surface of the hypatocy. the PCSK9 protein uh when it attaches to that LDL receptor, that receptor complex with LDL then is not broken up uh um is not dissociated and then the LDL receptor can't make its way back onto the surface of the hippaticide which is why blocking the PCSK9 actually allows for that cycle to continue. Um and is it about a 55 60% reduction in LDLC something like that right that's right yeah so so with uh Rapatha the injectable PCSK9 inhibitor yeah it's typically 55 to 60% and then this new oral version and listenide nobody's ever done the the applesto apples compar comparison against repatha but it seems comparable so 50 to 60% reduction in total LDL. That's right. Yeah. No, that's great. And for a country like ours, you know, South Asians, we for, you know, genetic and lifestyle reasons, we tend to accumulate more soft plaque versus hard plaque in our coronary vasculature and our cerebral vasculature as well. So, in the clinic, we are very aggressive with lowering uh APOB and LDL. you know, we want to see an LDL value well under 100 towards 70 and very high risk people, we'd like to see that number, you know, nearer to 50 milligrams per deciliter. Uh, combination therapy is effective and powerful. So that's a statin first line, a zettoi second line and now potentially I mean I'm hoping in the next 12 18 months or so if we can have an oral PCSK9 inhibitor to add to that uh
PCSK9 inhibitor to add to that uh repertoire toolkit uh it'll be a powerful a very powerful drug for us uh very powerful drug for us in India because it'll avoid the injections right the the other the current ones are all injectables uh which are self-administered subcutaneously but people are feel fearful, anxious, and there's a cost element to it as well. Yeah. that's right. I mean, I think that's that's the big uh plus to enlistide, which again is the the new newly approved oral PCSK9 inhibitor, is that it doesn't require the injections. Um just, you know, personal story, I started Rapatha, which is the injectable, about eight months ago now. And um and I did that in part because I had a CCTA with contrast and I had very very low calcified plaque and I had low soft plaque but I had the start of of cardiovascular disease. Like there was soft plaque there. Um and so I felt like it was just you know from my perspective I'd rather just do everything I can to keep it from getting worse then hopefully can revert that soft plaque. So um so the repatha for me first of all I think I get that a lot of people have have needle phobia. I did before I started you know using injectables it's really not a big deal but I do think the oral will help with that and it it reduced my uh LDL and apo by right about 60%. So it had the expected effect not on statins not on a zettoi you know this is just a a pcsk9 inhibitor monotherapy. So yeah, I mean I think combination potentially could could even drop it down further. So I'm I'm with you. I mean I think this is a good thing. Um and you know I I'm not quite at the level of saying that that you know heart disease is a thing of the past, but I do think if we were to get everybody who needed or who would benefit from these kinds of drugs on them, we would see a pretty like heart disease would no longer be the number one killer
would no longer be the number one killer in the United States uh or India. I don't know if it's number one in India, but it's usually heart disease and cancer that are one and two. I think heart disease would go way down the list. So we have the toolkit now to prevent heart disease from being a major killer, but it's a matter of getting it to the right people at the right time at a cost that's, you know, reasonable, affordable. Um, so I think there's lots of reason for optimism. It's unclear how long it's going to take to actually, you know, get those dominoes to fall. Yeah, I also remember uh reading uh some material recently on the same thread about the um uh the set P inhibitor, a molecule uh which is potentially being positioned to reduce the LP little A uh amounts as well. And again, you know, anecdotally, we have uh I think globally it's meant to be what 20% uh but I know from clinic we probably have 40 to 60% of people I see have elevated LP little and currently there's no molecule available to drive that value down and this is supposedly uh positioned to address that as well as another approach. Yeah. No. Yeah. That's a good point. I do wonder though, that's interesting that you see, you know, 40ish% in your clinical experience and and you know, there's this sort of people for a long time thought LP little A was 100% genetically determined. First of all, nothing's 100 well almost nothing's 100% genetically determined, but I think we're now learning that that there are environmental factors that move LP little A. And it makes me wonder if again like you had alluded to the dietary patterns or or other uh environmental features of the Indian population make that higher than than you might see, you know, in other other parts of the world. I don't know the answer to that, but it's it's interesting to think about. Um yeah the
about. Um yeah the I will I I'll add a data point which might uh strengthen that argument because what we've started to do over the last year is actually uh conduct serial LP little A values. So sort of the global approach was this is a genetic marker it's a screening tool you know just do it once in your life and it won't change much. uh we decided to measure this value this protein value longitudinally particularly those who are aggressively making lifestyle changes and or uh using a lipid lowering agent statin plus a zetami or a zetto alone and we have seen that LP little a values have begun to shift downward in those groups of individuals so I don't have you know hard data to tell you what those numbers are but I've seen it uh in a number of individuals that the LP little A value actually comes below the threshold of 30 uh milligrams um uh like per deciliter whatever the the unit is when they're making lifestyle changes and on a lipid lowering drug. So I think there is something in your statement there Matt. I don't think it's pure genetics alone. Yeah. And that fits very much with what I've seen as as well. So you can definitely move LP little A. I think we just don't 100% understand at this point, you know, why that's not true for everybody exactly what the right lifestyle or pharmacological approaches are to have that effect. The other thing that I want to just mention because I think this is relevant for the LP little A inhibitors as well as um enlistide is unlike rapa what we don't have for these things yet are the cardiovascular outcomes data. So enlisticide, this is interesting. Enlistide was actually approved based on the LDL lowering endpoint. We don't have the formal demonstration yet that that is leading to reduced cardiovascular events. I think everybody expects that will be the case, but with Rapa, we actually
the case, but with Rapa, we actually have that data. So it's just worth appreciating that, you know, this is based on a surrogate endpoint, so to speak, in that what we're really interested in is does this prevent people from having, you know, cardiovascular events. We don't know that yet. For enlistide, it would be surprising if it doesn't. Um but there are other examples with other types of diseases and and maybe this leads into our next topic where for example drugs that reduce body weight right don't always lead to reduced diabetes cardiovascular events things like that so that's still a little bit of an open question with both enlistide and the the LP little a um blockers so just worth people understanding that that point and that's only because enlisticide hasn't been used in patients long enough. That's why we don't have those cardio cardiovascular event outcomes yet. Yep, great point. Okay, let's talk about body weight because uh you know, everybody's excited. We talked about peptides already. Everybody of course is familiar with the GLP-1 agonist class of peptide drugs. Um there's now, you know, I guess three generations of GLP-1 drugs. uh you know there's the first generation which only targeted GLP the second generation like tzepide that target GLP-1 and GIP and now we starting to see things like retatride which actually target three different hormone receptors uh so um I know you're interested in retatride so maybe you can tell us about kind of what your your thinking is that and we're saying not yet FDA approved it's still in that process But um you know what is it that makes Reddit true tide potentially exciting a better version of the the fa the the generation one and generation 2 GLPs? Well I I think it's just triple
Well I I think it's just triple mechanism of action um which uh which is very powerful. I mean the the studies I've seen online have shown that uh what is it 26 28% net reduction uh in weight uh tending more towards fat. Uh just this morning um uh I had a conversation with a patient because it's not available in India and he has uh self sourced it from China. uh he's found a reputed uh manufacturer and he's going to be ordering it via a connect in Hungary. Got it from China and it's going to come in a few weeks and he's going to sell try it. So yeah, I I mean that so so that's interesting and maybe we're saying so what retatrite the third receptor it hits as the glucagon receptor, right? and so the idea there is that will potentially promote greater fat loss but like you alluded to uh fat burning, right? So oxidation of fat um in the liver which will in in theory increase energy expenditure in addition to suppressing appetite. So that's at least the the um anticipated mechanism of action for why having this this triple agonist uh could be better than the the dual agonists. Um I guess one question for you. So you mentioned this this patient of yours who is self-sourcing um Reddit True Tide. Um, and it's probably too early because we just don't have the data yet. But you know, I guess the question I've got is how many people are not getting the benefit they need from the generation one or things like tzepatide, the generation 2 that they really need to go to this third generation drug. Um, and I mean I think this is a question of sure bigger, stronger, faster, everybody
bigger, stronger, faster, everybody thinks that's better, but um, but is it? And and should we be going right to these more potent medications when it seems like we've got pretty good drugs that for a lot of people can get them to where they need to be when dosed properly, when, you know, people get the right education around diet and exercise and things like that. Just interested to get your thoughts. I get why the pharma companies want to keep pushing these these next generation drugs because because their patent life is going to run out. But is that the best thing for patients do you think? I think what piques my interest in this third generation molecule uh is that you know the legacy of generation one and generation two there is a strong narrative that the weight loss is index indexing towards muscle over fat. uh and here there was a narrative that is suggesting that the weight loss could be uh promoted via fat loss rather than muscle loss and metabolically we can all appreciate why that's more important uh for the individual uh holistically as well. So for me, uh that that's a very potentially a very powerful sort of clinical differentiator between generation one and uh and generation 2 for sure. I will say that uh you know in the last 18 months or so I suppose that people have now been actively using uh uh the first and second generations at least in India there has been a uh significant degree of maturity as to how important they look at holistic or comprehensive uh lifestyle changes as well. uh in the clinic we actually don't actively prescribe the GLPS uh we let the endocrinologists do that uh but what I do and what my team does is look at the supporting infrastructure around that individual to make sure that they're doing all the lifestyle things and increasingly people are now coming to us
increasingly people are now coming to us saying look before we start we want to ensure that this is a supportive mechanism so that we achieve better outcomes because people are appreciating that this shouldn't just maybe be a lifelong affair that there should be an exit ramp. So what's the minimal threshold of dose? How long do I need to be on it to see a benefit and then start to come off it and have a sustainable lifestyle uh which matches or allows me to elongate that value for a period of time. So that consumer shift is happening. Um and uh as I said for me the the only reason why I got excited about the third gen is the fat loss uh potential benefit. Yeah. Okay. that thank you that that's really good context and I agree 100% that that preserving lean mass and shifting the weight loss towards atapost as much as possible is is what we want to be doing. Um so it's my understanding that you know this is still a little bit ways out before there's the official approval. So, you know, leaving aside people sourcing this on the internet or China, wherever they're getting it, um, you know, it's sometime in 2027, maybe even 2028 before this is likely to get FDA approval. In part, and this is going back to the point I raised before about cardiovascular outcomes for uh uh the PCSK9 inhibitors. In part that's because they're I think they're waiting for those outcomes before FDA is going to approve uh reatride because in the case of body weight loss there are many examples of drugs that led to significant body weight loss but didn't actually improve outcomes and in some cases actually had negative uh outcomes. So you can lose body weight for lots of reasons some of which are good things some of which are bad things. And so FDA is a bit more careful I guess with the approval of weight loss drugs as opposed to you know LDL lowering lowering drugs. At least that seems seems to be the case. Um the other thing I thought was interesting and I'd be interested to get your takes
and I'd be interested to get your takes on this if you've heard about this or if you've thought about it at all is I read an article that um Lily who's the manufacturer of reatride is pushing to have FDA and there's even legal action going on now over this um regulate reatride as a biologic versus a small molecule and this is this gets into the bureaucracy of how FDA classifies drugs and you know at what point does a pep is a peptide long enough in terms of number of amino acids that it shifts from being a small molecule to a protein which is regulated as a biologic. So it's sort of a silly bureaucratic um thing but it has realworld impacts on how much the pharmaceutical company can charge for their drugs, how many years of patent protection they get. Um, so I don't know if you've heard about this at all, but here's my understanding is that that Lily originally uh uh asked FDA to regulate this as a biologic. FDA said no. Lily then sued FDA to because they didn't like that answer. And as best as I can tell, the reasons are that if it gets regulated as a biologic, they get four more years before Medicare, which in the United States is is, you know, one of the leading pricing components for for patients who get access to the drug. They get four more years before Medicare can negotiate on pricing. So, they can charge more. The US government can pay more. The US taxpayers can pay more. um and biologics aren't eligible for this 503A 503b compounding list that we talked about first off with with the peptides meaning that compoundingies would not be allowed to create compounded formulations of of reatrite so from a business perspective I get why they're doing that as a scientist I look at the structure of uh uh reatride compared to trazepatide compared to semaglutide and I'm
semaglutide and I'm there is absolutely no justification for putting these things in different categories. So this feels to me like a corporate bureaucratic, you know, swamp that has nothing to do with reality. Um, and maybe we'll, unless you have something more to say than that, maybe we'll just leave it at that. But it's it's just it's like this is so stupid. Why do we regulate drugs the way we do? It makes absolutely no freaking sense. Um but you know profit is I guess a big part of this and often times that seems to to be more important than than helping people. Um at least that's the way it feels. Uh let's talk about a different question though which is maybe more interesting than dealing with the mundane bureaucratic details. Um what do you think about the question of RGLP1s true longevity drugs? Oh. Um, no, that's not something I I've I've seen much information about at all. You're going to have to educate me on that, Matt. Yeah, I don't think we have much information. This is more more speculation. Um, I mean, I guess what I would say is here's here's what I think we can start to feel confident about is GLP seem to reduce risk of multiple age - related chronic diseases, right, in in humans. We don't know how broad that's going to be, but we've certainly got signal at least across a couple of major chronic diseases and and um early signal across things like you know cognitive decline um as well. So directionally suggestive I would say I haven't and and then the other I guess the other area we could think about uh to inform is we know in animal models the caloric restriction is is the most studied probably most robust intervention for slowing biological aging. One of the things that GLPS do obviously is reduce appetite reduce caloric consumption. So
appetite reduce caloric consumption. So from that perspective, you know, you could make a case that they they could be true longevity drugs. This also depends on how you define longevity. The dosing the the dosing would be uh different, right? This would be more of a micro doing uh I mean I don't know maybe yeah, it's an open question. Yeah, I would love to see nobody's done any experiments as far as I know. At least nobody's published yet. uh clear studies, preclinical studies in animals whether or not GLPS, you know, definitively increase lifespan, definitively slow biological aging. That's question number one. They will, I'm confident, because of the caloric restriction effect. Question number two you're getting at is if you could find a dose where you didn't reduce appetite, didn't reduce body weight, would you get benefits on biological aging or otherwise with the GLP-1 drugs? I just don't think anybody's done those experiments yet. This is a re this is an interesting case where we actually have more suggestive data in humans than we do in the animal models at this point for these things, you know, being true true longevity um drugs. So, it's yeah, I mean it's it's a little bit frustrating that we don't have any good preclinical data yet because we really should. I you know I know why the interventions testing program hasn't tested these drugs is that the interventions testing program just because of the the structure of that program is is pretty much limited to orally bioavailable uh drugs that you can mix with the mouse chow and so far nobody has demonstrated that you can do that with the GLP-1 in mice and and get the biochemical effect so that's why the ITP hasn't tested them I know GLPs have been suggested multip multiple times multiple people have put in proposals to test GLPs for the ITP. It just doesn't fit within the the framework that the ITP is sort of you know constrained to use right now for how they design their experiments. So I
how they design their experiments. So I guess I remember reading I I remember reading a I I think it was a systematic review that you had written a few years ago where you were studying the various forms of dietary interventions and calorie restriction being the most powerful one 25 30% reduction but then a conversation we had where I I think I asked well is that same effect replicable in a healthy individual versus someone who's on the standard American diet and metabolically unhealthy. Um uh and and wouldn't that also potentially be true here, which is, you know, should folks like you and I potentially who are, let's say, metabolically healthy, would we see any benefit of a GLP one or two or three, you know, inhibitor versus someone who's metabolically not healthy? I think that's a really good question. And again, I think it really boils down to whether or not there are calorie independent benefits from GLPs, right? In other words, if you could not have the appetite suppression and then ask the question, are there benefits associated with GLPS independent of caloric in intake? I think the answer is probably yes, but we just don't have definitive data at this point. So we know the receptor is present in other tissues and other organs but we don't really know for sure. So time will tell. I think this brings me to another topic well related topic though which um you know is something that I still I continue to be frustrated by which is you know if you think about so I'll ask you the question and you can tell me how how you think about this but I when you think about food right diet in people okay and and I think you can one simple way to break this out is is you know what you eat quality of diet how much you eat quantity calories in and when you eat you know getting restricted eating. In your view, how would you rank those three things? What you eat, how much you
three things? What you eat, how much you eat, and when you eat in terms of importance for the typical person? Obviously, everybody's different. There may be certain people where one of those is going to move, but but thinking at the population level like how do you think about the relative importance of those those three dimensions? It it would be in that order unless there are specific populations where you know we are looking for an acute change like a metabolic reset uh or a significant reduction in which case we'd change that around but otherwise you know I I think what you eat has to be the most important thing um uh whole food real food uh you know if you can locally locally sourced sustainable all that stuff. Um, and then how much of it and then the when. Yeah. And and I feel social media sort of flips it around. Exactly. And again, you know, this this again, I think almost every thoughtful person who actually has expertise in the space would agree with that. And yet what I see online are, you know, in some cases people who actually are knowledgeable, have credentials, and they talk about when you eat. And I'm like, stop it. You're confusing people. Tell people the truth. What you eat is way more important than when you eat. And it and and this is my view. If you're eating the diet you just laid out, which again I think most people would agree on that at least at a macro level, that's those are the things that are important. Whole foods, lots of vegetables, right? Make sure you get enough protein. How much is optimal, who cares? Make sure you get enough, right? Um, as long as you do that, how much you eat it for most people is going to pretty much take care of itself. It's really hard, I think, to become obese on a high quality diet. Not impossible, but difficult. And then when you eat
difficult. And then when you eat probably doesn't really matter for most people. Maybe it matters a little bit, but um so it's just it's frustrating to me that you know people are promoting this backwards for clicks cuz that's the only reason to do it. Not and so you know just just tell people the truth. Stop confusing people. Um so anyways, as you can tell I get a little bit worked up about that. But but I think but tell me you've looked at this you've you've looked at this research uh in so much detail I think what what have been your uh experiences and the data sets that you've seen around sort of the fasting mimicking diets and calorie restriction both in metabolically unhealthy and metabolically healthy people. Yeah. Well, so I mean I think the honest answer is we don't have a lot of highquality data at that granularity, right? Comparing metabolically healthy, metabolically un unhealthy. Um, and you know, the probably the best controlled human studies came from this calorie study, C A L E R I E, which was done at multiple sites, Pennington was one, St. Washington University, and St. Louis was one. um where they took different populations of people throughout the many years this was ongoing and looked at the effects comparing caloric restriction to exercise and this was not extreme caloric restriction. It was typically 20 to 30% reduction in calories. Um so they compared caloric restriction to exercise. They started with obese and metabolically perturbed individuals and then they moved to overweight individuals. it's kind of hard to get the ethical approvals to do a a true caloric restriction study in people who are optimal weight because then you're pushing them into what we would consider suboptimal weight, right? So there are reasons in addition to cost why it's difficult to do these studies. So I mean I think what we know with confidence is that caloric restriction in obese and metabolically
restriction in obese and metabolically perturbed individuals, diabetics in general is a good thing. Right? Maybe there are some individuals where that where you don't see the the improvements you would expect, but in general it's a good thing. One thing the calorie study showed which I thought was interesting is you can get the same effects from from exercise pretty much. Maybe not 100% across the board. Again, that's not shocking, right? That that's what you would see. But in humans, our data set is limited. So in mice what I think we can say with very high degree of confidence is that if you take mice that are fed an ad liibbitum diet we don't have a diet qual we don't have as much diet quality data because most mouse chows are already formulated much like you know companion animal food for you know what people think of as optimal nutrition right and all the growth factors and micronutrients and everything you need to be healthy so we don't have we what people typically do to look at bad diet is they do these diet induced obesity studies, right? Like a western diet. Of course, if you're inducing obesity in mice and you restrict calories, obesity is going to go down. So, yes, caloric restriction is beneficial, but it's also beneficial in mice on a normal diet for lifespan and for most health span metrics. So it really does seem to be the case that reducing mice from you know ad liibbitum eat as much as you want of this fortified diet you get benefits uh for longevity and they're very big. Um the timerestricted feeding studies though I think are also very clear. There is little to no benefit to timerestricted feeding unless they are also calorically restricted. Right? So if you allow the mice to eat the same amount as they would on a non-timerestricted diet, you don't get any benefit or if you do, it's tiny for lifespan. So then people are left looking for these, you know, trying to look around the edges for metabolic effects, insulin related effects. Maybe if you squint really hard, you can see some some metabolic benefits to
some some metabolic benefits to timerestricted eating that seem to be independent of the calories, but it's not completely convincing. And I sort of feel like the same thing's true in humans. The problem is in humans, you know, it's really hard to do very quantitative assessments of caloric intake, right? So you have to look you look at body weight, you look at things like that. But it my impression from the human data is there's not a lot of evidence for health benefits from timerestricted eating if the people are also not eating less. So again, the way I think about and again that could change like I'm open to having my mind changed. I haven't seen any data yet that's that's convincing. So where I land is I think timerestricted eating if that helps you not over consume food great do it. But don't make that the first order sort of intervention. The first order intervention should be look at what you're eating in terms of quality of food and focus on that first. I don't think timerestricted eating a a garbage diet has any benefit in in my view. Right. So that's kind of where I land in terms of ranking those those things. No, very much uh very very much aligned. Yeah. Um Okay. So, let's uh let's finish up. I want to talk about, you know, what what you've been up to. So, um I understand there's a couple things that I want to talk to you about. Um, so one is I hear you're doing a high altitude marathon, which sounds insane to me. And then I hear you're also on the, you know, more, uh, professional side working on uh, the first ever longevity market white paper for India. So, let's talk about both those things. Let's start with the uh, let's start with the marathon, right? Yeah. Um, it is officially the world's highest uh, marathon. It's in the state of Ladak which is the northernmost state here in India. Uh I did the half marathon there 3 years ago
did the half marathon there 3 years ago to celebrate my 40th birthday. This is how I like to celebrate my birthdays. Um and uh and this time around 3 years later I thought let me uh let me try the full version. So it's uh I hope we haven't jinxed it though Matt by talking about it online. Um I hope so too. But but so so tell me how high is this? What is the altitude you guys are at? Uh it's around 15, 000 ft. Uh so equivalency in meters is around 4 and a half to 5, 000 mu in terms of altitude. Yeah. Wow. Yeah. That I mean that's high. So so al people who who know altitude will recognize that's I mean that's that's way up there. I think that I think that's about the highest altitude I've ever been at in my life. And I tell you I felt it for sure. So I can't imagine running a marathon [laughter] at that altitude. But but you've been training for it, right? So you're Yeah, I mean I I've I've been running for a long time. Uh and um uh to to complete this event uh all the runners uh have to arrive at the location uh 7 to 8 days before the event so that your body has the opportunity to acclimatize whilst you're there. Um, and uh, clearly the time to complete the race is very, very different to doing a race at sea level. Um, but it's an incredibly scenic part of the world. I've I've been there many, many times. Uh, and it's very scenic. It's full of the mountains. It's uh, it's this very rugged, you know, almost lunarike uh, environment. So, I'm I'm very excited and hopefully the next time we're together, I'll have some some positive news to share. Yeah. Well, yeah, I'm looking forward to that. Wish you the best of luck. That's uh Thank you. That's pretty pretty impressive. Um okay, so tell us about this uh white paper that you're you're working on. Yeah, so it it's um uh unfortunately I'm you know there's an NDA so I can't say
you know there's an NDA so I can't say too much until it is actually released but uh okay it's it's the first uh it's the first white paper looking at the Indian market. uh we've uh as well as sort of the scientific work which is going on in the country, we're also looking at uh what's happening on the business end as well. So u next time around definitely it'll be published. It's just going through sort of that pre-publication and and drafting but next time around we'll definitely dive into it in in much deeper uh detail because you know frankly there's a lot of interesting stuff going on in the country. uh you know having been practicing here for so long now uh it's it's amazing to see and you guys saw it firsthand when you were you and Brian were out here uh this time last year right in India for the longevity conference so it's just the whole ecosystem has grown there's an entrepreneur energy technology chemicals all that you know drugs molecules so there's a lot going on so it should be a good paper yeah yeah I mean I know I told you this but but one of of the things that I took away from the the conference uh in Bangalore like you said about about a year ago was really h how I was really impressed with how not only how much energy uh there was and how much is happening in India but also how sophisticated the field the state of the field in in India was at that time and I'm sure that that's only continued so um so that's exciting looking looking forward to seeing that obviously huge uh opportunities in India and I think there's definitely definitely a place for India as a global leader in in the longevity space going forward. Um yeah, great. Anything we haven't touched on that you uh that you you want to talk about? No, I mean each time I see you, man, you look younger and younger. Uh [laughter] something. Well, I I appreciate you saying that. I'm not sure how true that is, but uh but I can tell you for sure I have not done any uh any cosmetic uh
not done any uh any cosmetic uh surgeries or any anything like that. that that's not in my future, I don't think. So, since we last met, which would probably have been about 3 months ago, have you added anything into your sort of your long health span uh stack? I don't think so. No, I mean, again, my my medications are what they've been for the past, you know, I don't know, six six, eight months since I started the PCSK9 inhibitor. I haven't added any any medications and supplements still pretty basic. I uh do creatine regularly, vitamin D, omega-3, B vitamins, and lithium. I think that's it. So, nope. Haven't added anything. Um Okay. [laughter] And again, I tend to be pretty conservative. What about you? Have you added anything in the last 6 months? I added Yeah, I've added uh Euro listen uh after the conversation we had because Brian uh was uh we spoke about it quite a lot last Yeah. So I've added your listen into that. I've just finished actually my three month stack. So for that so that's come uh that's come to an end. Uh and then uh for this month I mean obviously preparing for the marathon um I will be uh adding in uh NMN uh NR NR into my stack. Um uh for you know obviously conversation we just had and I will also be exposing myself to once or twice weekly uh IHD so intermittent hyperbaric hypoxic therapy. Uh so you know HBO is where you've just got sort of the pressure up uh and therefore driving oxygen in. IHT allows for a much more differentiated effect on the body. Um and this is again it's only once or twice a week. It's not going to be anything more than that but it's just in preparation to a high altitude sjourn
in preparation to a high altitude sjourn and and I'm going to just see if it gives me any edge on that. Yeah. Interesting. Yeah. Actually, I I forgot. I am also taking uh Rejuvenant, which is the time releaseleas calcium off ketoglutarate formulation, okay, in my supplements. So, um but that's I've been sort of doing that for for a while now. Uh and uh you know, again, it's like everything else, and we've already talked about this. It's not that I can say that I'm getting any, you know, consistent perceived benefit from it, but I the data on alpha ketoglutarate, particularly the time released and the rejuvenant formulation, it's all directionally in both animals and humans going in the right direction, the risk is essentially zero in my view. So, it's one of these things where even if I'm not 100% sold, the riskreward tilts toward towards reward. Um yeah the I I want to ask you about the the hyperbaric hypoxic uh treatment because this is I mean the hyperbaric oxygen therapy is obviously something that is also very popular among the same types of clinics that are doing NAD drips and some of these other you know what I call shiny object medicine. Um uh are there any risks to hyperbaric oxygen and and again I just wonder I mean you could certainly there could be risks in terms of like a a defy device malfunction or something like that. I think these things are built again if you're going to a reputable place that's pretty low but that is a possibility. Have you come across I I just you know I could imagine much like with the NAD drips these are pretty significant physiological perturbations that there could be risks for certain people. Uh so I just wonder if anything's come across your radar of even if the risk is even if these these events are rare are there any sort of significant adverse events that people should think about be aware of or possibilities. So in the 8 setting for people who are maybe not familiar with this this is
maybe not familiar with this this is hyperbaric oxygen therapy. So you're typically in an enclosed uh capsule where the pressure is dialed up and by dialing up the pressure you're increasing the partial uh pressure within that environment and therefore there's more oxygen which is uh uh being breathed in with every every breath. Uh now risks there as you said is device because it's a high concentration of oxygen uh in a pressurized space. Uh so that itself is a risk. So you want to make sure you're going to a reputed place. Number two is like diving uh you can have bar trauma of the tempanic membrane or damage uh to sort of the nasop ferings etc because there's a pressure difference which is being created um so you want to be careful about that and thirdly there's the the subjectivity of a claustrophobic space which some people just find too overwhelming uh because a lot of these are quite small and compact uh in in smaller clinics uh in terms of the exposure to the oxygen levels I haven't seen seen any specific you know adverse event or side effect. Um the uh the oxygen is typically a high flow which is provided by the mask similar to what you might get in a hospital setting. Uh and uh you're breathing it in normally just in a slight in a pressurized environment. So I haven't seen any or read myself of any sort of adverse events but if anyone watching this has please do share that. I'm always happy to uh continue the education and and learn more about it. Um this however is very different to IHT because with IHT you're not sitting in a pressurized room. You're in a normal room. You have a device which is the size of sort of a a vacuum cleaner and it has a mask which attaches to the face. And this oxygen concentrator has the ability to change the partial pressure of oxygen. So it either dials it up and it goes up to I think a P2 of 36 you know oxygen
think a P2 of 36 you know oxygen concentration right now at sea level is about 21% of room air. So it dials it up to 36% as a concentration and it dilutes it down to about 8 to 12% depending upon the brand. Got it. Uh which is the equivalency of of sort of sitting at every base camp that sort of altitude. Got it. uh and um I used it sort of in the initial test just to uh just habituate myself before writing out the protocol and I did notice that at the lowest end of the oxygen um unlike when you visit altitude and your body has the opportunity to acclimatize over time to a lower and lower partial pressure here you are exposing the body rapidly to a low concentration and that leads to a hyper a ventilatory drive, a tacky cardic drive and sort of a tightness in the chest as well. So, it can feel uncomfortable. The good news is that you can alter the uh the titration. So, you don't have to go all the way down to eight to dilute. You can go to 16. You can then bring it down to 14, 12, and as you get comfortable with it, you can change it. And at any time, you can just switch it off um or just take the mask off. It's that simple. Um but I would advise caution with IHT particular to individuals who have respiratory conditions or cardiovascular conditions because you don't want to trigger such low concentrations of oxygen that it suddenly drives a tachi card response and and leads to an adverse event. So I'm much much more careful with IHT versus HBOT. Yeah. Great. Thank you for that. And is that a device that you you can buy and have in your home or do you go to a clinic where you do it? I mean HBOT uh is is a more expensive device and it requires space. So typically uh you know you very affording individuals might install it in their homes but otherwise it's clinic based. The IHT is a fraction of that cost. Uh
The IHT is a fraction of that cost. Uh it's probably around uh you know 20, 000 15 to $ 20, 000 US for the machine. So, it's it's considerably cheaper than the HOT device. And uh I I now know of people who are sort of buying it at home and keeping it there for personal consumption as opposed to having to go into a clinic and utilize it. Yeah. Got it. All right. Well we'll have to wait and see how your marathon time is and then we can judge whether or not, you know, that's a good investment or not. The good news, Matt, is it's going to be a PV either way. So, uh it's going to be my first [laughter] All right, great. Well, wish you the the best of luck on that and look forward to uh to hearing about your victory in the high altitude marathon. Thanks, Marcus. This has been a ton of fun as always and looking forward to uh to doing this again in another month or two and hopefully Brian will be able to join us next time around. Super. Thanks so much,
Transcript auto-generated by YouTube. Verbatim — duplicates intentionally preserved.
Matt Kaeberlein and Marcus Ranney offer a useful rhythm for the field: look at the signal, separate it from the noise, and keep healthspan anchored in evidence rather than enthusiasm.
A single approval, policy shift, or adverse event can dominate attention. The question is what it means in the wider body of evidence. Oral PCSK9 inhibitors, GLP-1 drugs, NAD discussions, and compounded peptides each sit at different levels of certainty.
A grounded reader does not need to dismiss innovation. They need to understand where confidence is strong, where the evidence is early, and where safety must lead.
Longevity is not simply about extending years. It is about preserving function: cardiovascular capacity, muscle, cognition, metabolic stability, and independence. Interventions matter when they protect those capacities.
That lens keeps the field honest. A therapy that changes a biomarker is interesting. A practice that preserves a life worth living is meaningful.
The episode’s discussion of peptides and NAD is a reminder that “natural,” “regenerative,” and “longevity” are not safety guarantees. Delivery method, dose, oversight, and patient context matter.
Evidence-based medicine is not slow for its own sake. It is careful because the body is complex.
"The future of longevity will belong to practices and therapies that can survive careful evidence."
"Healthspan is the measure that keeps longevity honest."
"A promising mechanism is not the same as a proven outcome."
"Caution is not cynicism. It is respect for biology."
Separate interventions with strong human outcome data from those supported mainly by early or mechanistic evidence.
Use biomarkers as context, not as the entire definition of health.
Be especially careful with peptides, infusions, and experimental therapies outside qualified medical supervision.
